Clinical Outcome and Reverse Epidemiology

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Many recent studies have suggested that protein-energy malnutrition and inflammation in maintenance dialysis patients are associated with a decreased quality of life and increased hospitalisation and mortality, especially from cardiovascular diseases [10,27,28,123]. Epidemiological studies indicate that hypoalbuminaemia and increased serum CRP are strong predictors of poor clinical outcome in the CKD population [36, 37]. Compared to traditional risk factors, such as obesity, hypercholesterolaemia, and hypertension, hypoalbuminaemia per se, which is generally considered an indicator of MICS, has one of the most striking and consistent associations with the prediction of clinical outcome in these individuals [146].

In highly industrialised, affluent countries, protein-energy malnutrition is an uncommon cause of poor outcome in the general population, whereas over-nutrition is associated with a greater risk of cardiovascular disease and has an immense epidemiological impact on the burden of this disease and on shortened survival. In contrast, in maintenance dialysis patients, under-nutrition is one of the most common risk factors for adverse cardiovascular events [22, 117, 147]. Hence, certain markers that predict a low likelihood of cardiovascular events and an improved survival in the general population, such as decreased body mass index (BMI) [73-75, 148, 149] (Fig. 4) or lower serum cholesterol levels [49, 87], are risk factors for increased cardiovascular morbidity and death in dialysis patients [117]. Obesity, hypercholesterolaemia, and hypertension appear paradoxically to be protective features that are associated with greater survival of dialysis patients. A similar protective role has been described for high serum creatinine and total homocysteine levels in these patients [150].

The association between under-nutrition and adverse cardiovascular outcome in dialysis

Fig. 4. Reverse epidemiology of obesity in maintenance haemodialysis patients. Association between changes in BMI over time and cardiovascular mortality in a 2-year cohort of 51 841 maintenance haemodialysis patients [149]

Body Mass Index Categories (kg/m2)

Fig. 4. Reverse epidemiology of obesity in maintenance haemodialysis patients. Association between changes in BMI over time and cardiovascular mortality in a 2-year cohort of 51 841 maintenance haemodialysis patients [149]

patients, in contrast to the case in non-dialysis individuals, has been referred to as 'reverse epidemiology' [117]. The aetiology of this inverse association between conventional risk factors and clinical outcome in dialysis patients is not clear. Several possible causes have been hypothesised, including survival bias and time discrepancy between competing risk factors (under-nutrition vs over-nutrition). However, the presence of MICS in dialysis patients offers the most plausible explanation for the existence of reverse epidemiology. Protein-energy malnutrition, inflammation, or the combination of the two are much more common in dialysis patients than in the general population, and many elements of MICS, such as low weight-for-height or BMI, hypocholestero-laemia, or hypocreatininaemia, are known risk factors of poor outcome in dialysis patients [117]. The existence of reverse epidemiology may have a bearing on the management of dialysis patients. It is possible that new standards or goals for such traditional risk factors as BMI, serum cholesterol, and blood pressure should be considered for these individuals.

The phenomenon of risk-factor paradox is caused or at least accentuated by MICS in several ways. First, patients who are underweight or who have a low serum cholesterol, creatinine, or homo-cysteine, may be suffering from the MICS and its poor outcome. Thus, MICS may both cause these alterations and also be associated with increased mortality, either caused by the illnesses that engender MICS or by atherosclerotic cardiovascular disease that seems to be promoted by MICS [27, 151, 152]. Second, the above paradoxical factors may indicate a state of under-nutrition, which may predispose to infection or other inflammatory processes [22]. Finally, it has been argued that when individuals are malnourished, they are more susceptible to the ravages of inflammatory diseases [153]. Hence, any condition that potentially attenuates the magnitude of protein-energy mal nutrition or inflammation should be favourable to dialysis patients. Suliman et al. reported a more specific example of the contribution of MICS to risk-factor reversal concerning hyperhomocys-teinaemia in dialysis patients [154-156]. In their study, plasma total homocysteine levels were shown to be dependent on nutritional status, protein intake, and serum albumin in haemodialysis patients. Dialysis patients with cardiovascular disease had lower plasma homocysteine levels as well as a higher prevalence of malnutrition and hypoalbuminaemia than those without cardiovascular disease. Furthermore, in another study, plasma total homocysteine was shown to rise during treatment of malnourished peritoneal dialysis patients who were given a daily exchange of an amino-acid-containing peritoneal dialysate (containing 1.7 g methionine) [157]. The puzzling inverse relationship between low blood pressure and poor outcome in the dialysis population might also be accounted for by nutritional status and/or inflammation. Iseki et al. [158] showed a significant association between a low diastolic blood pressure, hypoalbuminaemia, and risk of death in a cohort of 1243 haemodialysis patients who were followed for up to 5 years. The death rate was inversely correlated with diastolic blood pressure, which per se was positively correlated with serum albumin and negatively correlated with age. Hence, hypotension may in some cases be a manifestation of MICS in dialysis patients.

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