Division of Nephrology, Department of Medicine University of California Davis, and the Department of Veterans' Affairs Northern California Health Care System, Davis and Mather, CA, USA
Predictors of mortality in dialysis patients
Mortality of patients with end-stage renal disease (ESRD) remains a significant problem, with most deaths resulting from cardiovascular disease [1]. Several of the most powerful predictors of mortality in cross-sectional studies are what are regarded as nutritional markers; most notably serum albumin and serum creatinine [2], respectively markers of visceral and skeletal protein mass. Prealbumin (transthyretin), a further nutritionally regulated protein [3,4] also powerfully predicts mortality both in peritoneal [5,6] and haemodialysis patients [5]. These observations have been used to support a hypothesis that malnutrition is the proximate cause of mortality. Such a hypothesis would suggest that we could feed our way out of morbidity and mortality in our patient population. Unfortunately we have been unable to do so. Why have we failed and where shall we go?
Malnutrition and inflammation cause similar changes in nutritional measures
Malnutrition is generally diagnosed by finding specific changes in serum protein composition or in anthropometric measurements that occur in the presence of inadequate protein and/or calorie intake rather than by directly assessing nutritional intake. Specifically, reduced serum concentrations of albumin, prealbumin (transthyretin), and retinol binding protein, or loss of muscle mass are used as indicators of malnutrition. The major difficulty probably arises from the fact that many of the causes of these changes in serum protein composition and of changes in body composition and structure that have traditionally been assumed to result from inadequate protein and calorie intake (malnutrition) are in fact the consequence of inflammation instead, or result from a combination of malnutrition and inflammation. Albumin, like other nutritional markers such as prealbumin [68] and transferrin [9,10] is a negative acute-phase protein [11]. The synthesis of these proteins decreases during inflammation, as does their serum concentration, changes that occur entirely independently of nutritional state [911]. Albumin concentration in dialysis patients is negatively correlated with levels of positive acute phase proteins [1214]. These are proteins whose synthesis and serum concentration increase during inflammation (C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, ferritin). Such an increase is regulated by and results from increased concentrations of the cytokines interleukin (IL)-6, and tumour necrosis factor alpha (TNF-) [15,16]. These markers of inflammation are statistically powerful determinants of albumin level in ESRD patients [1214,17].
Other clinical markers normally used to diagnose malnutrition are found to be present simultaneously with markers of inflammation. Stenvinkel [18] established that patients with pre-ESRD who were judged to be malnourished by measurement of subjective global assessment (SGA) also had markers consistent with the presence of inflammation. Both CRP and fibrinogen were significantly greater in groups of patients with SGA 2.
Inflammation predicts vascular disease
Disturbingly, the prevalence of vascular disease, judged by the prevalence of carotid plaques and elevated intimamedia area, was also increased in this cohort. In this context, both Zimmerman et al. [19] and Yeun et al. [20] found that overall mortality and cardiovascular mortality were significantly higher in patients with elevated CRP or SAA. In the latter study the inclusion of CRP in the regression model eliminated albumin as a predictor of risk [20]. These findings are mirrored by a recent series of publications looking at the association between cardiovascular risk and CRP levels in patients without renal disease [21,22].
The relationship between markers of inflammation such as CRP, SAA, and IL-6 and serum albumin concentration is also found in peritoneal dialysis patients [14]. In this population transperitoneal albumin losses also contribute importantly to serum albumin concentration; however, transperitoneal albumin loss is entirely independent of markers of inflammation [14]. While some patients with high losses of albumin across the peritoneal membrane may also be inflamed, this is only by chance. As in the haemodialysis population, markers of inflammation in peritoneal dialysis patients also predict death [23].
One important unresolved question is whether inflammation is the cause of cardiovascular disease, or a marker of existing disease, or both. Review of that topic is beyond the scope of this paper. Intrinsic to that argument is the question of identification of the source of inflammation. Some argue that vascular disease is itself an inflammatory process [21] and that the markers of inflammation reflect existing vascular disease. This would suggest that inflammation is a reflection of rather than a cause of vascular injury. Inflammation, however, affects plasma protein and lipoprotein composition in ways that suggests that it may indeed promote vascular injury.
How to appraise inflammation and malnutrition in the presence of the other
It is a difficult task to distinguish patients who have pure protein calorie malnutrition from patients with an admixture of inflammation and malnutrition. Even more difficult is the distinction from patients who indeed are consuming what would normally be accepted as adequate calorie and protein intake, yet appear by standard assessment to be malnourished. It is critical to evaluate these patients for the presence of inflammation and their actual nutritional intake separately. Part of the assessment of malnutrition, including hypoalbuminaemia, should be measurement of protein catabolic rate.
If one assumes that normalized protein catabolic rate is a reflection of dietary protein intake, then there is a population of dialysis patients who have low albumin levels caused by inadequate dietary protein intake who have no evidence of inflammation. Similarly there is a group who have no evidence of reduced nitrogen catabolism, low albumin levels and have evidence of inflammation. Most patients probably have both to varying degrees. The processes are independent. Nutritional requirements may also be increased for patients facing the challenge of systemic inflammation.
The rate of albumin synthesis is dependent partially upon availability of amino acids [11]. Albumin synthetic rate increases promptly upon re-feeding amino acids even if total protein and calorie deficits (malnutrition) persists. Thus, persistence of hypoalbuminaemia despite adequate nutritional intake is evidence for non-nutritional causes of hypoalbuminaemia. Other proteins, such as retinol binding protein, transthyretin, and insulin-like growth factor 1 (IGF-1) all increase quickly following nutritional supplementation [24,25] and are good markers to assure that nutritional supplementation has indeed been adequate. However, the simultaneous presence of inflammation and malnutrition confounds the use of these markers [26]. When healthy volunteers were subjected to semi-starvation (1500 kcal/24 h) for 24 weeks, serum albumin decreased only moderately (from 4.28 to 3.86 g/dl) in spite of a marked 23% reduction in body weight (from 69.3 to 53.6 kg) and muscle mass [27]. This suggests that when serum albumin concentration is reduced to very low levels, additional processes, most likely inflammation, contribute. It is difficult to depress serum albumin concentration to less than 3.0 g/dl in the absence of both inflammation and malnutrition.
If inflammation can be ruled out, then ambiguous surrogates for malnutrition are most probably valid. The major problem is establishing nutritional status in the presence of systemic inflammation.
Source of inflammation
The evaluation of a patient with an increased CRP should include a careful interval history and physical examination including a careful assessment of the vascular access. If no correctable infection source is found, it is unclear how to proceed further. It is possible that aspects of the dialysis procedure such as the water source, the dialyser type, or other processes are responsible for inflammation. Identification of this as a source will require further research. Another potential source is clinically masked infection in the vascular access. The presence of infection in grafts may require [111In] white cell scans [28] or other procedures to appreciate. Suppression of inflammation may be useful if infection can be excluded, but this will require a carefully controlled prospective clinical trial, since the risk of unmasking a silent infection in these immunosuppressed patients is great. At this time deliberate use of anti-inflammatory agents specifically to treat elevated CRP levels without another indication is unwarranted and is to be discouraged outside the context of a clinical trial that includes informed patient consent. A diligent search for potential infection, however, is prudent.
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Acknowledgments
This work was supported in part by the research service of the United States Department of Veterans Affairs, in part by a grant from the National Institutes of Health RO1 DK 50777, and in part by a gift from Dialysis Clinics Incorporated.
Notes
Correspondence and offprint requests to: George A. Kaysen MD PhD, Chief Division of Nephrology, University of California Davis, TB 136, Davis, CA 95616, USA.
References