Serum albumin concentration in dialysis patients: Why does it remain resistant to therapy?

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1 Kidney International, Vol. 64, Supplement 87 (2003), pp. S92 S98 Serum albumin concentration in dialysis patients: Why does it remain resistant to therapy? GEORGE A. KAYSEN Department of Medicine, Division of Nephrology, University of California-Davis, Davis, Califonia; and Research Service, Department of Veterans Affairs Northern California Health Care System, Mather, California Serum albumin concentration in dialysis patients: Why does it remain resistant to therapy? Serum albumin, transferrin, and prealbumin levels decrease as glomerular filtration rate (GFR) declines, even prior to the start of dialysis. The levels of these serum proteins are also associated with creatinine levels and lean body mass. Lean body mass also decreases with advancing renal failure. While all of these measures are regarded as reflections of nutritional status, each are strongly associated with any of several indicators of inflammation: positive acute-phase proteins or the cytokines that regulate their synthesis rate, in both longitudinal and cross-sectional studies. Inflammation in turn is associated with comorbid conditions, cardiovascular disease, chronic infections, age, and vascular access type. Additionally, dialysis patients are subjected to oxidative stress and exposure of blood to foreign antigens in the dialysis process that also potentially contribute to inflammation. In otherwise healthy individuals reduced protein and calorie intake does not cause hypoalbuminemia since albumin fractional catabolic rate (FCR) and resting energy expenditure (REE) normally decrease in response. The simultaneous occurrence of decreased protein intake and inflammation prevent these homeostatic compensations to reduced nitrogen and energy intake from occurring, resulting in decreasing albumin, transferrin, and prealbumin levels and loss of muscle mass. Nutritional intake may also be challenged as a result of renal failure associated with anorexia, gastroparesis, and socioeconomic factors, which may all cause nutritional intake to be sufficiently marginal so that the combined effects of inflammation and decrease protein intake are expressed as decreased visceral and somatic protein stores. Albumin levels are lower in dialysis patients than among the general population and are a powerful predictor of mortality [1]. There has been little or no progress in increasing albumin levels in the prevalent dialysis patient population in over 10 years, despite the wide introduction of biocompatible dialyzers and a trend toward increasing dialysis dose [2]. Albumin levels are controlled by the rate of albumin synthesis, albumin fractional catabolic rate (FCR), and albumin distribution Key words: albumin, creatinine, prealbumin, inflammation, interleukin-6, C-reactive protein by the International Society of Nephrology between the vascular and extravascular compartment. These in turn are affected by both nutrition [3] and, since albumin is a negative acute-phase protein, by inflammation [4]. Additionally, plasma volume expansion can dilute the plasma pool. A rather profound reduction in both calorie and protein intake is, however, not generally associated with reduced levels of albumin or prealbumin (transthyretin) in otherwise healthy individuals [5], suggesting that factors other than reduced protein, and calorie intake alone, play a role in altering serum protein levels in patients with chronic kidney disease. What are these factors and what are the prospects for improving nutritional status in dialysis patients? Prior to the initiation of dialysis both protein and calorie intake generally decline [6]. The evidence for this is from measured reduction in urinary urea nitrogen appearance, dietary records, and the increased incidence of reduced serum concentrations of albumin and transferrin, both nutritional markers. Preservation of calorie intake during consumption of a low-protein diet is, however, not associated with hypoalbuminemia in this population, if otherwise healthy [7, 8]. Why then is reduction in protein and calorie intake reflected in alteration of serum protein composition? One explanation for this is that both albumin and transferrin are also negative acutephase proteins. MALNUTRITION ARISES FROM PROCESSES BEYOND INADEQUATE NUTRIENT INTAKE ALONE While calorie and protein intake are less than optimal in patients as they approach end-stage renal disease (ESRD), the magnitude of reduced nutrient intake is insufficient, that if acting alone should result in decreased levels of visceral or somatic protein mass. In a study conducted in Minnesota over 50 years ago, healthy volunteers were subjected to semi-starvation (1500 kcal/ 24 h) for 24 weeks. Despite a 23% reduction in body weight (from 69.3 to 53.6 kg) and muscle mass, serum S-92

2 Kaysen: Serum albumin concentration in dialysis patients S-93 Fig. 1. Relationship between normalized protein catabolic rate (npcr), C-reactive protein (CRP) level, and serum albumin concentration in 287 hemodialysis patients. Note that the relationships are nonlinear. The relationship between albumin and CRP is above a value of 12 mg/l and between albumin and npcr is below a value of approximately 1.0 g/kg/day. Data and figure are adapted from [40] with permission. albumin decreased only moderately (from 4.28 to 3.86 g/dl) [9]. This study suggested that when serum albumin concentration was reduced to very low levels that additional processes contribute. It is unusual to find serum albumin decreased to values less than 3.0 g/dl in the absence of both inflammation and malnutrition. One may use normalized protein catabolic rate (npcr) as a surrogate of nitrogen catabolism, which at steady state should approximate dietary nitrogen intake. Using this assumption, one finds that the serum albumin concentration is described by a surface relating the independent effects of npcr and with the levels of the acute phase protein C-reactive protein (CRP) (Fig. 1). These relationships are nonlinear. Unlike what occurred in the controlled Minnesota study [9], and what is described for subjects with pure anorexia nervosa, as npcr declines in dialysis patients, so does serum albumin concentration, and the quantity of this decline is dependent upon the incident level of CRP (Fig. 1). These observations suggest that dialysis patients are subject to stresses beyond protein and calorie restriction alone, and that one important factor in this relationship is that imparted by inflammation. At progressively greater levels of CRP, serum albumin concentration decreases even if npcr values are high (Fig. 1). These observations must be viewed in the context that the lower limit of sensitivity of the assay for CRP employed in this study was approximately 5 mg/l and thus may mask clinically significant levels of inflammation, well into the range where CRP predicts cardiovascular disease [10]. Thus, dialysis patients are sufficiently inflamed so that their serum protein concentration is influenced by nutrition, far more so than would be expected of an individual without underlying inflammation. Ikizler [11] observed in hospitalized dialysis patients that npcr greatly overestimated nitrogen intake. Thus, hospitalized dialysis patients were, in addition to having a lower than acceptable npcr, in negative nitrogen balance. Thus, it is possible that in the presence of acute disease or inflammation that npcr may actually overestimate protein intake, masking negative nitrogen balance. The major problems with the nutrition only model of hypoalbuminemia in dialysis patients are the observations that both short-term fluctuations in serum albumin concentration [12], as well as stable and longlived decreases in serum albumin concentration [13, 14], are accompanied by evidence of activation of the acutephase response, but not of significant changes in npcr. While this may reflect a mismatch between nitrogen consumption and catabolism, it is very clear that during periods of inflammation albumin synthesis is suppressed [15], and the fractional rate of albumin catabolism is greater than would normally occur [13] for a given level of serum albumin concentration [3], suggesting that albumin levels are strongly influenced by the effects of inflammation, regardless of nitrogen availability. INFLAMMATION IN RENAL FAILURE The average levels of acute-phase proteins are increased in dialysis patients when compared to normal subjects or to patients not yet on dialysis [16, 17]. Inflammation is strongly associated with cardiovascular risk in the general population [10, 18] and in patients with renal failure as well [16, 19, 20]. Indeed, when analyzed by multiple regression analysis, CRP levels replace albumin as a predictor of all-cause and of cardiovascular mortality [19]. As renal function declines so does dietary protein and energy content [6]. While there are several factors that may play a role in the anorexia that accompanies progressive loss of renal function, npcr increases following initiation of hemodialysis treatment [21] and so does serum albumin concentration. A component of the increase in the prevalent dialysis patient is the attrition of the most malnourished patients [22]; however, among the survivors, albumin levels do increase during the first year [22]. This may well be a result of improved nutrition or to the removal of uremic toxins. However, this is then followed by a decline in both parameters. The low albumin levels that are encountered in incident dialysis patients are likely a consequence of a combina-

3 S-94 Kaysen: Serum albumin concentration in dialysis patients tion of protein-calorie malnutrition, inflammation, and plasma volume expansion, which are present just prior to the initiation of dialysis therapy [23]. Albumin concentration and npcr both increase during the first six months of dialysis therapy [24], suggesting that correction of the nutritional factors indeed has a salutary effect on albumin levels. However, after the first year, albumin levels decline [21, 25]. This may be due to a loss of residual renal function or the accrual of comorbid conditions that have the potential to suppress appetite or to activate the systemic inflammatory response, or both. RESPONSE TO REDUCED NUTRIENT INTAKE IN THE PRESENCE AND ABSENCE OF INFLAMMATION Hypoalbuminemia does not normally occur in otherwise healthy but malnourished individuals until near terminal starvation [5]. One mechanism for preservation of tissue mass is a reduction in resting energy expenditure (REE) [5, 26, 27]. Similar mechanisms occur in uninflamed dialysis patients [28], suggesting that renal failure, per se, does not disrupt these homeostatic mechanisms. By contrast, patients with wasting and infection with the human immunodeficiency virus (HIV) exhibit an increased REE that is even more marked in the presence of diagnosed infection [29]. This is also true of patients with chronic lung disease [30], cancer [31, 32] and in patients with renal failure [28, 33, 34]. Harty [35] noted that there was no relationship between REE and nutritional state among peritoneal dialysis patients and suggested that this inability to conserve energy may act as an additional risk factor for ongoing malnutrition. The most parsimonious explanation for the failure of patients with renal failure from reducing REE appropriately is that they, like patients with other chronic illnesses, are subject to the systemic inflammatory response [16, 36]. One mechanism whereby inflammation impairs the capacity of patients to defend their albumin mass is by the interaction between inflammation, albumin FCR, and serum albumin level. When protein intake is reduced, so is albumin synthesis [3, 37 39]. As albumin levels decline in response to the decrease in synthetic rate, so does albumin FCR [3]. This normal homeostatic mechanism acts as a counter-regulatory support in the presence of reduced protein and calorie intake. Albumin FCR is directly proportional to the serum level of longlived acute-phase proteins in dialysis patients independently of albumin concentration [13]. However, if one adjusts albumin FCR for the level of either the longlived acute-phase protein 1 acid glycoprotein or ceruloplasmin (Fig. 2), the relationship between albumin level and albumin FCR described in the absence of inflammation [3] reappears [13]. Thus, inflammation and nutrition interact in at least two ways to alter albumin concen- Fig. 2. Relationship between albumin fractional catabolic rate (FCR), serum albumin concentration, and ceruloplasmin concentration in 64 hemodialysis patients at the time that albumin FCR was measured by the disappearance of [ 125 I] human serum albumin. Albumin FCR was the percent of the plasma albumin pool catabolized per day. Plasma albumin pool was the product of plasma albumin concentration and plasma volume. Individual data points by open circles. Data obtained from [13]. tration, through their effects on both albumin synthesis and FCR. Using normalized protein catabolic rate (npcr) as a measure of protein intake, we have established an interaction between npcr and serum albumin concentration if controlled for a marker of inflammation, either CRP [16, 40] or serum amyloid A (SAA) [41]. While albumin level was independently correlated with both npcr and the level of these acute-phase proteins, the acute-phase proteins were more strongly and independently associated with albumin levels than was npcr (Fig. 1). NUTRITIONAL AND NON-NUTRITIONAL FACTORS INTERACT TO CONTRIBUTE TO CHANGES IN PLASMA AND BODY COMPOSITION Complicating the relationship between measures of nutritional outcome (serum albumin, transferrin, prealbumin levels, lean body mass) and dietary energy and protein intake is the association between hypoalbuminemia and other comorbid conditions that are either associated with inflammation or with hypoalbuminemia independently of inflammation. Comorbid conditions that are associated with low albumin levels [42], diabetes, peripheral vascular disease, smoking, neoplasms, and either temporary vascular access or A-V grafts are also associated with increased prevalence of infection [43, 44] or with inflammation. Dialysis patients also have in-

4 Kaysen: Serum albumin concentration in dialysis patients S-95 Fig. 3. Relationships between inflammation, decreased nutrient intake, protein, malnutrition, and change in serum protein composition and muscle mass. Inflammation and malnutrition lead to decreased synthesis of visceral proteins. Cytokines, as well as uremic toxins, also reduce appetite, adding to the effect of inflammation on visceral protein levels. Tumor necrosis factor (TFN ) also causes apoptosis of adipocytes and decreases muscle protein synthesis, impeding recovery from malnutrition. creased incidence of infectious diseases, such as tuberculosis [45]. Age and volume overload [46] also are independently associated both with hypoalbuminemia and with inflammation. In addition to their direct effect on serum protein concentration, cytokines [47, 48] and other comorbid conditions suppress appetite, as well as increase a patients vulnerability to the effects of malnutrition (Fig. 3). Additionally, gastric emptying disorders are associated with diabetes and other comorbid conditions common in dialysis patients and may directly affect nutrient intake [49]. Another factor associated with loss of renal function is the development of metabolic acidosis as a result of reduced renal acidification. Metabolic acidosis also can suppress albumin synthesis [50] and promote skeletal muscle catabolism [51, 52]. Thus, it might also be reasonable to speculate that metabolic acidosis plays a role in causing both hypoalbuminemia and loss of muscle mass in dialysis patients, thus providing an additional therapeutic avenue to approach. THE EFFECTS OF NUTRITIONAL STATUS ARE LONG LASTING AND MAY RESULT FROM DIFFICULT-TO-REVERSE PROCESSES Nutritional status prior to the onset of dialysis predicts survival both in the short-term [53], and even after five years of follow-up [42]. Furthermore, while nutritional status improves within the most malnourished patients during the first year of renal replacement therapy, baseline measures of malnutrition predict that serum albumin and prealbumin values will remain low even after a year of dialysis [54]. Other investigators have found no improvement in albumin levels during the first year of treatment with hemodialysis [21]. Thus, either the effects of malnutrition are long lived in this population or malnutrition reflects other morbidity that may not be easily reversible, or both. Following the first year of dialysis no clear trend in serum albumin values is evident [55]. In contrast to albumin values, measures of somatic protein mass, creatinine [40], phase-angle [55], a measure that correlates with lean body mass, decrease with time. The change in creatinine [40] is associated with CRP levels, while the changes in phase angle correlate with the cytokine interleukin-1 (IL-1 ) [55], suggesting a cumulative effect of the inflammatory response. Comorbidity is strongly associated with hypoalbuminemia in the dialysis patient population [22, 42 46]. Many of these factors, such as vascular disease and chronic obstructive pulmonary disease (COPD), are not readily reversible, but most likely contribute indirectly to malnutrition by their association both with anorexia and inflammation. Other factors, such as vascular access type, may be more amenable to therapy. Not surprisingly, albumin concentration tends to decline among patients in the six months prior to death [22]. Inflammation may both directly reduce measures that are used to establish nutritional status (lean body mass, serum albumin, and prealbumin levels), and also affect nutritional intake, making it appear that the two are linked, while instead each has an independent effect (Fig. 3). Associations between dietary protein intake (or npcr as a surrogate marker) and hypoalbuminemia may not then be causally linked. Renal failure, per se, leads to increased levels of leptin [56 58] and other possible appetite suppressive substances [59, 60], making it difficult to maintain nutritional intake at desirable levels in patients with ESRD. Cytokines also directly suppress

5 S-96 Kaysen: Serum albumin concentration in dialysis patients appetite. Therefore, care must be taken in interpretation of cross-sectional associations. WHAT IS THE EFFECT OF IMPROVED NUTRIENT INTAKE? Cano [61] compared lean body mass, predialysis creatinine, prealbumin, and albumin levels in a group of diabetic and non-diabetic patients and found that, while all of these parameters were significantly reduced in the diabetic patients, npcr was not in comparison to the non-diabetic subjects. Interventional experimental data therefore is necessary to establish the effect of nutrition as compared to associations between nutrient intake and manifestations of clinical malnutrition in patients. These data have provided mixed results. Were protein malnutrition the principal cause of hypoalbuminemia in the dialysis patient population, one would expect that nutritional supplementation would be effective in restoring albumin pools, as it is in patients with hypoalbuminemia caused by protein malnutrition [3, 62]. Such associations have not been uniformly demonstrated [63, 64]. Oral nutritional supplements or intradialytic parenteral nutrition (IDPN) have proved either ineffectual [62, 63, 65] or only partially effective [66, 67] in repair of hypoalbuminemia of hemodialysis patients in some studies. Others have had positive effects on both albumin and prealbumin levels [68, 69], although these studies were longitudinal using baseline data as the control, rather than a prospective randomized study with a control group. The mixed results of nutritional intervention in correcting hypoalbuminemia suggest that other factors may be more important, even dominant in causing reduced albumin concentration in most or a large fraction of dialysis patients, or at least other factors require resolution before marked improvement in nutritional status can be achieved. DIALYSIS DOSE: CAN MORE BE DONE? Dialysis dose also had no effect on outcome once a sufficient dose was achieved [70, 71]. When dialysis dose is inadequate, increasing doses may be associated with increasing npcr, suggesting reduction in anorexia an improving nutritional intake; however, this was not substantiated in the large prospectively randomized HEMO study. Thus, improving dialysis dose beyond a urea reduction ratio of %, a single-pool Kt/V , and the equilibrated Kt/V is unlikely to produce great benefit with regard to nutritional outcome. The caveat that must be added to this is that in women, who have small urea volume of distribution, there was a survival benefit, suggesting that some benefit might accrue individuals having low volume of distribution of urea (Vd urea), but generally one can conclude that greatly increasing dialysis dose using the current model of thrice weekly dialysis is unlikely to have a dramatic impact on survival or nutritional outcomes. METABOLIC ACIDOSIS Metabolic acidosis has been demonstrated to cause a decrease in the rate of albumin synthesis in acute studies [50]. Of interest, in patients with renal failure, serum bicarbonate levels are nearly uniformly found to be inversely correlated with serum albumin concentration [22, 72, 73]. Kirschbaum [74] reported that methods of collection of serum specimens for laboratory analysis in dialysis units may lead to artifactually low measured levels of bicarbonate. While this effect would lead to reduced precision in the relationship between bicarbonate and albumin levels, it would not explain the strong inverse relationship observed. Interventional studies, likewise, have not demonstrated a robust positive effect of correction of metabolic acidosis on serum albumin concentration [75, 76]. Since dietary acid and protein are generally linked, it is likely that the statistical correction for the interaction between dietary protein and serum bicarbonate is insufficient to correct for its biologic effect. SOCIAL AND ECONOMIC FACTORS CONTRIBUTING TO MALNUTRITION Social and economic issues that may play a role in inadequate nutritional intake may provide a fruitful avenue to approach. Leon et al [77] used a systems-based approach to improve nutritional intake in dialysis patients that has been successful in improving actual nutritional outcome measures even when controlled for inflammation (CRP levels). Both retrospective [78] and prospective studies [79] of nutritional supplementation suggest that dietary intervention has the potential to effectively correct the progressive malnutrition in dialysis patients. Unlike cytokine- or uremic toxin-induced anorexia, social and economic barriers to access to adequate nutrition are solvable given adequate resources to solve these problems. CONCLUSION Malnutrition, at least as defined by reduced levels of albumin, prealbumin, and transferrin, is a result of combined effects of inflammation and inadequate protein and calorie intake. The causes of inflammation are several, but include comorbid conditions that may not be immediately reversible. In addition, both inflammation and comorbid conditions suppress appetite, which further confounds efforts to improve nutritional status. Small non-randomized studies suggest that nutritional

6 Kaysen: Serum albumin concentration in dialysis patients S-97 supplementation may have some salutary effect. Efforts aimed at reducing sources of inflammation such as increasing the use of fistulas and identifying and treating infections may prove of value, while it does not appear that increasing the dose of dialysis beyond currently recommended values will likely have a salutary effect. While metabolic acidosis may contribute also to malnutrition, clinically, the added effect of protein that normally accompanies metabolic acid on balance leads to improved nutritional status in most patients with acid retention. ACKNOWLEDGMENTS This work was supported by grants from the National Institutes of Health RO1 DK 50777, and by the Research Service of the Department of Veteran s Affairs. Reprint requests to George A. Kaysen, M.D., Ph.D., Chief, Division of Nephrology, University of California Davis, One Shields Avenue, TB 136, Davis, CA gakaysen@ucdavis.edu REFERENCES 1. 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