Chronic kidney disease (CKD) is an irreversible and progressive disease state leading to renal dysfunction and related morbidity . According to the National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines, CKD is defined as a chronic disease state in that irreversible, structural, or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), are present for at least three consecutive months . The degree of renal insufficiency, based on the magnitude of the estimated GFR for 1.73 m2 body surface, is used to classify the CKD into five stages: (1) GFR > 90 ml/min, (2) GFR 60-89 ml/min, (3) GFR 30-59 ml/min, (4) GFR 15-29 ml/min, and (5) GFR < 15 ml/min . If they survive long enough, CKD patients eventually reach stage 5 CKD, also known as end-stage renal disease (ESRD), in which life prolongation is exclusively dependent upon renal replacement therapy, i.e. maintenance haemodialysis or peritoneal dialysis treatment and/or kidney transplantation. However, the majority of CKD patients die before reaching ESRD .
Epidemiological data indicate that there are currently at least 20 million individuals with CKD in the US , including over 300 000 ESRD patients who undergo maintenance dialysis. Diabetes melli-tus accounts for half of all cases of ESRD in industrialised nations . According to the estimates of the US Renal Data System (USRDS), the number of ESRD patients will surpass one-half million by 2010 and will be between 1.5 and 3.1 million by 2030, whereas the US population will grow only from 280 to 350 million over the same 30-year period . This exponential growth has major public health implications, especially since ESRD patients consume a disproportionately large component of the US Medicare budget, due to their requirement for continuous renal replacement therapy and their frequent morbidity [5, 6]. Despite many years of efforts and improvement in dialysis technique and patient care, the mortality rate in maintenance dialysis patients in the US and most industrialized countries continues to be unacceptably high, currently still approximately 20% per year in the US and 10-15% in Europe and Japan [7-9]. CKD and ESRD patients also commonly have a high hospitalisation rate and a low self-reported quality of life [10-13]. Cardiovascular, cerebral-vascular, and peripheral vascular diseases comprise the bulk of the severe morbidity and mortality in CKD patients [14, 15]. Indeed even a slight increase in serum creatinine (an often clinically used marker of renal insufficiency) has been shown to be an independent risk factor for cardiovascular disease and atherosclerosis in the general population [16-18].
Among potential candidates to explain the high rate of morbidity and mortality and cardiovascular disease in CKD patients, wasting syndrome and cachexia continue to top the list. Epidemiological studies have repeatedly and consistently shown a strong association between clinical outcome and measures of both protein-energy malnutrition [19-22] and inflammation in CKD patients [23, 24]. Hypoalbuminaemia, rather than such conventional risk factors as hypertension and hypercholesterolaemia, is one of the strongest risk factors for mortality among dialysis patients (Fig. 1). Almost half of all dialysis patients have a serum albumin < 3.8 g/dl, which has been shown to be associated with at least a two-fold increase in mortality . However, it is not known whether hypoalbuminaemia is a reflection of malnutrition, inflammation, or both. Many
>4.2 4.0-4.2 3.8-4.0 3.6-3.8 3.4-3.6 3.2-3.4 3.0-3.2 <3.0 Serum albumin groups
Fig. 1. Association between serum albumin concentration and all-cause mortality in a 2-year cohort of 56 920 maintenance haemodialysis patients . After dichotomising albumin values based on the cutoff level of 3.8 g/dl,the unadjusted and case-mix adjusted HR for serum albumin < 3.8 g/dl was 2.40 (95% CI: 2.31-2.48) and 2.19 (95% CI: 2.10-2.26), respectively 
investigators have observed that these two conditions tend to occur concurrently and coexist in individuals with CKD, and many factors that engender one of these conditions also lead to the other [22, 23, 26, 27]. Therefore the term 'malnutrition-inflammation complex (or cachexia) syndrome' (MICS) [22, 28] or 'malnutrition-inflammation-atherosclerosis' (MIA) syndrome  has been proposed to indicate the combination of these two conditions in such patients and their associations with atherosclerotic cardiovascular disease and poor outcome (see below).
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