点击显示 收起
1 From the Department of Medicine, University of Texas, Galveston.
2 Address reprint requests to WE Mitch, Department of Medicine, 4.124 John Sealy Annex, 301 University Boulevard, University of Texas, Galveston, TX 77555. E-mail: wmitch{at}utmb.edu.
See corresponding article on page842.
What can cross-sectional evaluations teach us about a group of individuals? In my view, results from such evaluations should lead to testable hypotheses about mechanisms that cause abnormalities present in the group. For patients with chronic kidney failure (CKF), cross-sectional evaluations have yielded subnormal serum protein concentrations and body weight because of a decrease in body fat and protein stores (1). These results have led to widespread agreement that many CKF patients, especially hemodialysis patients, are malnourished. This diagnosis indicates that the mechanism for these abnormalities is an insufficient or imbalanced diet, but the story is much more complicated than the label of malnutrition implies (2). What is needed are new strategies providing insights into the genesis of these abnormalities and greater precision in the measurements that form the basis for the associations uncovered and, hence, the extrapolations offered to explain why the abnormalities occur.
For example, one interesting association noted in cross-sectional is a link between a low serum albumin concentration or weight loss and a high circulating concentration of acute phase reactant proteins such as C-reactive protein (CRP). The implication is that inflammation causes a loss of protein stores and that inflammation is common in CKF patients. This concept was soon expanded to include inflammation as a principal risk factor for the excessive incidence of atherosclerosis-associated problems experienced by CKF patients (1). Although cross-sectional results indicate that CKF patients do have high circulating concentrations of cytokines, neither the source of inflammation nor the mechanism that increases the concentrations of these cytokines has been identified. Moreover, circulating concentrations of CRP and other cytokines are also high in elderly patients and in patients with congestive heart failure or diabetes (3–5). This finding raises questions about readily accepting the conclusion that a high circulating CRP concentration indicates chronic inflammation in vascular tissues and that it is the mechanism causing loss of body protein. CKF patients not being treated with dialysis have high concentrations of the same cytokines as do dialysis patients, so the sole mechanism for this observation cannot involve exposure of the patient’s blood to dialysis membranes (6, 7). In brief, both the mechanism causing high concentrations of acute phase reactant proteins and the response of serum albumin to the removal of inflammatory stimuli need to be investigated.
What about the measurements leading to a diagnosis of malnutrition? First, there are substantial difficulties in interpreting the results from many of the cross-sectional studies, because, in these studies, CKF patients were compared with healthy adults rather than with patients with chronic illnesses who were taking a variety of medicines. Second, the evaluation of abnormal values is difficult because the within-patient degrees of variability for each of the multiple measurements are rarely included in these studies. Most troublesome is that the effects of other factors on measurements such as variability in the diet (or the degree of exercise) within each patient or the group of patients are rarely included in these studies. Some of these problems can be addressed by evaluating changes in body weight and other indexes in a longitudinal study.
In this issue, Johansen et al (8) undertook a year-long evaluation of wasting in hemodialysis patients. They began by enrolling 54 patients in a protocol that included a single, initial evaluation of the diet with a food-frequency questionnaire, which was followed by anthropometric and biochemical measurements made every 3 mo plus another questionnaire directed at evaluating physical activity and muscle strength. No significant changes in body weight, fat mass, fat-free mass, or serum biochemical markers of physical performance were found. However, a decrease in estimated body cell mass—as assessed by bioelectric impedance analysis—was observed, and body cell mass was inversely correlated with serum interleukin 1ß concentrations. A decrease in activity status (on the basis of data from the questionnaires) was also found, but no significant decrease in physical performance measures was observed. The inverse relation between serum concentrations of CRP and albumin was confirmed. The problems that emerged are important: a complete set of observations was possible in only 31 of the 54 patients. (Is this the reason for so many cross-sectional rather than longitudinal evaluations?).
Johansen et al did not evaluate potential causes of the problems experienced by dialysis patients (2). For example, in experimental uremia, metabolic acidosis stimulates the degradation of protein in muscle, leading to loss of muscle mass, whereas insulin deficiency accelerates muscle protein loss independently of acidosis (2, 9). In uremic patients, including those treated by dialysis, correction of acidosis suppresses the accelerated degradation of protein and leads to increases in body weight, in muscle mass (assessed by anthropometry), and in serum albumin concentrations (2). In healthy and diabetic adults, insulin administration suppresses protein breakdown. Thus, Johansen et al could have evaluated the degree of acidosis and the diabetic or insulin status of their subjects. Also, their dietary evaluation provided only limited information; for example, protein and calorie intakes were not documented, which could have changed during the study, especially in patients with inflammation, which can suppress appetite. In addition, there are potential problems with the use of bioelectric impedance analysis for assessing lean body mass in hemodialysis patients, because body water changes during dialysis. Moreover, Johansen et al did not report the within-patient variability of the technique (10, 11). Finally, the number of patients in their study was limited, and the reported changes in anthropometric, biochemical, and activity measurements were small. These shortcomings make it difficult to derive hypotheses about the mechanisms of any abnormalities.
The study by Johansen et al is important, however, because it was a serious longitudinal evaluation of dialysis patients that provides information about the stability of measurements. In addition, some of their results could point to new strategies to be tested. Regarding mechanisms, does an exercise program correct the decrease in physical activity and actually improve physical performance or insulin responses? Does exercise influence leptin or other markers of inflammation (12)? Does correction of acidosis improve appetite, insulin responses, or physical activity? Admittedly, such evaluations will be difficult, but these investigators showed that longitudinal studies can be completed. With such studies, our understanding of the causes of abnormalities noted in cross-sectional studies of CKF patients will improve and will prompt testing of strategies directed at correcting the problems.
REFERENCES
Related articles in AJCN: