JN 2000; Vol.13 N°4: 249-259

Review

JNEPHROL 2000; 13: 249-259

Assessment of inflammation and nutrition in patients with end-stage renal disease

Burl R. Don, George A. Kaysen - Division of Nephrology, University of California Davis Medical Centre, and Department of Veteran's Affairs, Northern California Health Care System, Sacramento (CA) - USA

ABSTRACT: Malnutrition commonly occurs in patients with end-stage renal disease (ESRD), and hypoalbuminemia is considered the best clinical marker of malnutrition and mortality in this population. Recently, it has been recognized that a substantial number of patients with ESRD have serologic evidence of an augmented inflammatory response and moreover, inflammation may be as or more important than protein intake in causing hypoalbuminemia. In addition, the presence of inflammation may be a more powerful predictor of mortality than dietary protein intake. The presence of inflammation is often subtle and is detected by increased levels of the positive acute phase proteins, most notably C-reactive protein. The causes of the stimulation of the systemic inflammatory response may include reaction to dialyzer membranes, increased production of advanced glycosylated end-products, oxidative stress of uremia and overt and occult infections, especially unrecognized arteriovenous graft infections. There is a complex relationship between inflammation and nutritional status. Inflammation can cause both anorexia with protein-calorie malnutrition as well as wasting through mechanisms mediated by cytokines. Novel therapies will need to be developed to counter this systemic inflammation since it appears to be a major cause of mortality in patients with end-stage renal disease.

Key words: Albumin, C-reactive protein, Cytokines, Arteriovenous graft infections, Acute phase proteins, Advanced glycosylated end-products, Oxidative stress

Introduction

It is stated in many reviews that protein and calorie (energy) malnutrition occurs commonly in patients with end-stage renal disease (1-3). Depending on the parameter measured, the prevalence of malnutrition in the chronic dialysis population ranges from 10 to 54% (4-10). Clinicians, using hypoalbuminemia as their principal nutritional marker, have recognized for many years that their malnourished dialysis patients had a poorer prognosis. This has been substantiated by a growing body of evidence linking poor nutritional status in the dialysis population with increased morbidity and mortality. It may not be justifiable, however, to use simple laboratory markers, or indeed even physical evidence of loss of lean body mass as proof of malnutrition, if one uses malnutrition to mean inadequate nutritional intake.
Steadman's Medical Dictionary, 1995, defines malnutrition as: "faulty nutrition resulting from malabsorption, poor diet, or overeating" (11). By this definition, when the term malnutrition is applied to a patient with end-stage renal disease the presumption is that the patient's condition is a result of poor protein and calorie intake. Implicit in this definition is the presumption that all can be corrected by providing adequate nutritional treatment. The terms malnutrition and wasting syndrome are used frequently and interchangeably to describe the gradual attrition in the physical and mental status and increased morbidity that is seen in significant subset of patients with end-stage renal disease. As per the definition of "malnutrition" it is important to address the question as to whether these "malnourished" dialysis patients do indeed ingest inadequate calories and protein or instead are there other non-nutritional processes involved? There are a number of observations that have challenged the traditional definition of malnutrition in dialysis patients. For example, increasing protein and caloric intake does not consistently improve traditional nutritional parameters in patients with end-stage renal disease (12,13). Serum albumin concentration has been widely used as the best clinical marker of malnutrition and has been touted to be the most convincing link between malnutrition and mortality (14); yet, as will be discussed below, there are factors other than malnutrition that are frequently more important in reducing serum albumin levels than is an inadequate ingestion of protein. It has long been known that albumin synthesis is effectively and rapidly reduced during inflammation (15) leading to hypoalbuminemia. Recently, it has been recognized that a substantial number of patients with end-stage renal disease appear to have serologic evidence of augmented inflammatory state (16) and moreover, it appears that inflammation may be as or more important than protein intake in causing hypoalbuminemia (17). In addition, clinical wasting is not the unique province of malnutrition. This is illustrated by the fact that consumption was the term applied in the last century to patients with tuberculosis, which is the clinical prototype of chronic inflammation. As we better understand the association between patient outcomes and nutritional status, what is emerging is an understanding that there is an interplay, interdependence and interaction between caloric and protein intake and the inflammatory state in patients with chronic renal failure that contributes to both a wasting syndrome and increased morbidity and mortality.

Indices of Malnutrition

One of the most difficult problems in clinical nephrology is how do we objectively measure the nutritional state of our dialysis patients. Several indices have been used to quantify malnutrition in patients with ESRD (Tab. I). What is clearly apparent from an initial review of this list is that no single parameter can accurately measure nutritional status. In addition, many parameters (serum albumin, transferrin, pre-albumin, lymphocyte count, and skin test reactivity) that are used to measure nutritional status may more truly measure alterations in the inflammatory response and are not true measures of impairment in protein and caloric intake. This does not detract from the fact that inflammation may cause anorexia with an attendant reduction in protein and caloric intake. Furthermore, inflammation may, by increasing energy demands, also alter basic nutritional needs (18,19) as well as can increase host susceptibility to infection. Thus inflammation and nutritional intake and state are interrelated in a complex way.
The distinction between whether a given nutritional index reflects augmented systemic inflammatory response or impaired caloric intake may have clinical importance in evaluating and treating a patient on chronic dialysis, in deciding on whether the abnormal indice is due either to poor caloric intake or to a more generalized inflammatory process or to both. Despite these caveats about interpreting measures of nutritional state, it is clear that true malnutrition (impaired protein-caloric intake) is a major problem in renal failure patients based upon the indices that may more truly reflect dietary intake, although even here, it is necessary to directly measure nutritional intake in order to prove the presence of a nutritional basis for a change in body habitus.

TABLE I

1. Serum albumin concentration

2. Transferrin

3. Serum cholesterol concentration

4. Lymphocyte count

5. Skin test reactivity

6. Subjective global assessment

7. Pre-albumin concentration

8. Anthropometric measurements

9. Body composition (bioelectric impedance or DEXA)

10. Body weight relative to ideal body weight

11. Serum creatinine concentration

12. Blood urea nitrogen concentration

13. Dietary intake history

14. Total body nitrogen

15. Protein catabolic rate

Relative body weight (observed body weight /ideal body weight), skin fold thickness (body fat), mid-arm circumference, total body nitrogen, serum cholesterol, protein catabolic rate (surrogate for low protein intake) are reduced significantly in dialysis patients as a group compared to normal control subjects (14, 20, 21). Of these, only protein catabolic rate can be considered an unambiguous nutritional marker, since each of the others can be reduced in conjunction with inflammation. The National Cooperative Dialysis Study (NCDS) (5) conducted during the late 1970's noted that 27 % of the 165 dialysis patients studied had midarm muscle circumference below the fifth percentile. Thunberg et al (4) evaluated 58 non-diabetic dialysis patients and reported that 62 % of the patients had reduced triceps skin fold thickness which is a proxy for fat stores. Others (6-8, 22,23) have reported similar decreases in traditional anthropometric measurements. Using the technique of neutron activation, Schilling et al (24) and Pollock et al (23) reported that total body nitrogen was significantly lower in dialysis patients (75-88 % of the normal range). Reduction in total body nitrogen may be a sensitive marker of protein deficiency.
In a seminal study by Kopple and his associates, it was shown that a caloric intake of 35-38 kcal/kg/day is required to maintain normal protein-energy metabolism in hemodialysis patients (25). Moreover, the average dietary protein intake to maintain normal nitrogen balance is closer to 1.2 g/kg/day. The NCDS (5) and others (6, 10, 23, 24) have reported that the average caloric intake in chronic hemodialysis patients in the range of 23 to 29 kcal/kg/day and dietary protein intake was approximately 1 g/kg/day. Thus, both caloric and protein intake in dialysis patients is far below requirements to stay in adequate nitrogen and energy balance. Analysis of dietary protein and energy intake during the Modification of Diet in Renal Disease Study (MDRD) suggest that caloric and protein intake diminish long before the patients begin dialysis (26). Spontaneous reduction in dietary protein intake was observed when the glomerular filtration rate was 30-35 ml/min/1.73m². This reduction in protein intake was associated with decreases in serum albumin, transferrin, body weight, mid-arm muscle area and percent body fat. Other clinical indicators of reduced dietary protein intake include lower levels of pre-dialysis levels of serum urea nitrogen and creatinine, and these parameters are associated with increased morbidity (27) and mortality (14), repectively.
Bioelectric impedance (BIA) and dual-energy x-ray absorptiometry (DEXA) have emerged as more sophisticated measures of body composition and nutritional status. BIA is a method of detecting certain electrical properties of living tissue such as resistance and reactance and deriving quantification of body composition. Although BIA has been touted to be able to estimate lean body mass and body cell mass, its strength is in determining total body water (28). DEXA determines body composition by measuring the differential attenuation of bone, fat and lean (water-rich) tissue to low- and high-energy radiograph beams. Preliminary nutritional intervention studies suggest that DEXA may be a sensitive measure of changes in body composition in dialysis patients (28). Dietary protein and caloric intake as estimated by dietary history and recall has been shown to be an inaccurate tool to assess nutritional status. The NCDS showed a poor correlation between dietary protein intake as estimated by the history obtained from the patient and the changes in urea concentration and protein catabolic rate as measured by standard urea kinetic formula (5). The subjective global assessment (SGA) has been promoted as a simple and reliable tool to evaluate nutritional status in dialysis patients. The SGA score is based on the presence of five historical parameters (weight loss, gastro-intestinal symptomatology, dietary food intake, functional capacity and co-morbidities) and three anthropometric measurements (skin fold thickness, arm and leg circumference and the presence of edema) (29). The CANUSA study on dialysis adequacy, nutrition and mortality in 680 chronic ambulatory peritoneal dialysis patients showed a tight association between the SGA score and mortality (30). Although the SGA is used as a marker of nutritional status, a recent study by Stenvinkel et al (31) noted a strong relationship between the SGA score and C-reactive protein levels. Thus, like albumin, alterations in the SGA score may be a consequence of, more than just protein and calorie malnutrition. Another major criticism of the SGA is lack of consistency, and differences in experience between clinical observers performing the evaluation.

Malnutrition and Morbidity and Mortality

It is said that the presence of protein and calorie malnutrition in dialysis patients is a powerful predictor of high morbidity and mortality (2). The indices that have been associated with increased mortality include decreased serum albumin concentration (14), urea nitrogen appearance, and low pre-dialysis serum concentration of cholesterol, urea and potassium (20,21). Chertow and Lazarus (32) reviewed the literature and found 13 studies that examined the relationship between nutritional indices and morbidity and mortality in dialysis patients. What is the most striking conclusion in their review is the predominance of hypoalbuminemia as the most significant marker of mortality in patients with renal failure. For example, the paper by Lowrie and Lew (14) was a landmark study in evaluating the association between this commonly measured laboratory variable and one-year mortality in more than 12,000 hemodialysis patients. After adjusting for the effects of age, race, cause for the primary renal disease and the presence of diabetes, serum albumin concentration was the most important predictor of patient mortality. The more sophisticated measures of body composition (DEXA and BIA) may prove to be powerful tools to identify patients at risk for increased morbidity and mortality, and longitudinal studies are currently underway to provide this data. The main factor that requires clarification is to establish the cause of altered body morphometry, i.e. to sort out independently the effects of malnutrition from those of inflammation.

Albumin Metabolism in Chronic Renal Failure

Since the serum albumin concentration is such potent predictor of morbidity and mortality, it is important to understand the factors and processes that may alter serum albumin levels. Several processes may results in hypoalbuminemia; redistribution of albumin into the interstitium, decreased synthesis, increased catabolism or exogenous loss of albumin (33). The primary causes of hypoalbuminemia in the dialysis patient population are reduction in the rate of albumin synthesis (34) and external loss, either into hemodialysate or across the peritoneal membrane. Although loss of albumin across hemodialysis membranes can be significant, especially with extensive reuse with bleach (34,35) and contribute to hypoalbuminemia, these losses are avoidable. External losses of albumin may however be an important cause of hypoalbuminemia in peritoneal dialysis patients, given that external albumin losses with this modality of dialysis average 4 to 5 g/1.73 m²/day and can be considerably greater in magnitude (36-38). Increased catabolism of albumin does not appear to be a significant cause of hypoalbuminemia in dialysis patients (39).
Decreases synthesis of albumin appears to be the major cause of hypoalbuminemia in hemodialysis patients and to a lesser extent in peritoneal dialysis patients. Given that albumin synthesis is at least in part regulated by nutritional status, hypoalbuminemia has generally been used as a marker of malnutrition. This over-simplification of the regulation of albumin synthesis has until recently obscured the other major cause of reduced albumin synthetic rate, namely inflammation.
Albumin is synthesized exclusively in the liver (40). Three independent processes have been implicated in suppressing the albumin synthetic rate in patients with chronic renal failure; metabolic acidosis, impaired protein intake and inflammation. First, the metabolic acidosis, that is so pervasive in chronic dialysis, has been reported to decrease albumin synthesis (41) and increase protein breakdown (42-44). Moreover, correction of metabolic acidosis has been shown to increase serum albumin levels in hemodialysis patients (45). However, a recent prospective, randomized control trial in hemodialysis patients has failed to show an improvement in serum albumin concentration with partial correction of the acidosis (46) and the various cross-sectional analyses have not found a direct correlation between serum albumin and bicarbonate levels (34, 38, 47). Second, decreased amino acid substrate availability, as seen in dialysis patients with poor protein-caloric intake, will suppress albumin synthesis resulting in hypoalbuminemia and the attendant increased morbidity and mortality. The previously prevailing concept was that inadequate dialysis led to anorexia, which in turn caused decreased protein-calorie intake (5, 27). It has been demonstrated that increasing the amount of dialysis (Kt/V) will increase protein intake providing a basis for this hypothesis (48). Kaysen et al (34) and Owens et al (49), however, have shown there is no correlation between the serum albumin level and the dose of dialysis. In addition, we found that measures of protein intake and body composition were similar between a group of 6 hypo- and 6 normoalbuminemic patients (34). Teehan et al (20) have reported similarly that serum albumin concentration did not always correlate with protein intake. Although it is apparent that nondiabetic patients with protein malnutrition and hypoalbuminemia will have improvement in serum albumin concentrations when given nutritional supplementation (50), there is substantial conflicting data as to whether nutritional supplementation improves serum albumin levels in dialysis patients (51-53). Finally, an emerging concept is that many patients with chronic renal failure have chronic intermittent activation of the systemic inflammatory response (54). This leads to a complex combination of physiologic immunologic and metabolic effects, termed "acute phase response", which includes the suppression of albumin synthesis (34). In a large group of patients we found that inflammation (levels of the major acute phase proteins C-reactive protein (CRP) or serum amyloid A (SAA)) was the most powerful factor in predicting serum albumin levels in a cross sectional study of both hemodialysis (55) and peritoneal dialysis patients (37). Indeed, if CRP is included in the regression model, CRP but not albumin predicted all death as well as cardiovascular death in hemodialysis patients (56). These observations have raised the concept that the direct correlation between serum albumin and mortality reflects the presence of other comorbid conditions, specifically inflammation and/or cardiovascular disease.

Inflammation and Chronic Renal Failure

During the last ten years, several investigators (16, 57, 58) have shown that a significant percentage of chronic hemo- and peritoneal dialysis patients have increased levels of inflammatory mediators including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor * (TNF *) suggesting that the systemic inflammatory response is an important part of the clinical physiology of chronic dialysis patients. Using conventional clinical criteria, as defined by the Society of Critical Care Medicine and highlighted by Bistrian in his recent review (54), the systemic inflammatory response is present when any two of the following criteria are met: a temperature greater than 38 °C or less than 36 °C, pulse rate greater than 90 beats per minute, white blood cell count greater than 12,000 or less than 4000 cells/L or bands in excess of 10%, respiratory rate greater than 20 breaths/minute and partial pressure of carbon dioxide less than 32 mm Hg when breathing room air. In our experience however, many chronic dialysis patients with biochemical evidence of an augmented inflammatory response do not show these overt clinical criteria of systemic inflammation. Thus, the inflammation we see in our dialysis patients can be subtle and insidious and easily missed unless attention is paid to measurements of acute phase proteins or cytokines. Given that dialysis patients with increased levels of CRP (a proxy for systemic inflammation) have an increased mortality, identifying patients with biochemical evidence of inflammation appears to have clinical importance and should prompt a careful search for potential reversible causes (see Sources of Inflammation below).
The inflammatory response begins with release of IL-1 and TNF* by monocytes and macrophages that subsequently activates a complex cascade of other inflammatory mediators including IL-2, IL-6 and IL-8 (59-62). The release of cytokines leads to both the stimulation and inhibition of protein synthesis. These so-called acute phase proteins have served as important biochemical markers of inflammation. IL-1 and TNF* stimulates the production of the positive acute phase protein which include CRP, SAA, ferritin, haptoglobin, complement 3 and *₁-acid glycoprotein. IL-6 augments the synthesis of fibrinogen, *₁-antitrypsin and *₂-macroglobulin (63). Cytokines can also inhibit the synthesis of proteins (negative acute phase proteins), most notably serum albumin and transferrin.
The observation that serum albumin is a negative acute phase protein supports the contention that serum albumin is actually a marker of inflammation. Hemodialysis patients with hypoalbuminemia have increased serum levels of CRP, ferritin and *₂-macroglobulin compared with normoalbuminemic patients (34). Bergstrom et al noted that CRP was a more powerful predictor of mortality for hemodialysis patients than hypoalbuminemia (64). After adjusting for CRP levels, low serum albumin lost its ability to predict mortality. Other investigators have noted that IL-6 and TNF-* correlated with low serum albumin levels, and using multivariate analysis, IL-6 was the strongest predictor of mortality. Both CRP levels (37, 55) and cytokine levels (61) are predictive of albumin concentration in cross-sectional studies, and also predict survival (61).
Using multivariate analysis, we have evaluated the relative importance of inflammation and protein intake on serum albumin concentration in a cross-sectional study in chronic hemodialysis patients. Increased CRP levels and low dietary protein intake were both independent predictors of hypoalbuminemia (Fig. 1) (55). This data suggest that both inflammation and nutritional factors are responsible for the low serum albumin concentration. Moreover, a recent longitudinal study by Ikizler et al (65) demonstrated that inflammation as assessed by CRP concentrations, and nutritional status, as indicated by reactance values (marker of lean body mass), were independent predictors of hospitalizations in chronic hemodialysis patients.
The studies mentioned thus far have demonstrated an important association between inflammation and nutrition and increased mortality and morbidity, but have not established how these parameters lead to these untoward consequences. It is known that atherosclerotic cardiovascular disease (AVD) is the major cause of morbidity and mortality in patients with chronic renal failure undergoing renal replacement therapy (66, 67). The reasons for the increased prevalence of AVD in the dialysis population is not well understood and may be due to factors such as increased incidence of diabetes mellitus, hypertension and hyperlipidemia. Several large cross sectional studies have identified CRP as an independent risk factor of cardiac disease in both men and women (68-70). In the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) study, CRP predicted future risk of coronary heart disease in initially healthy middle-aged men (71). In another study, the sub-population of men who benefit from aspirin were those with elevated CRP levels (70). Thus, serum CRP levels and presumably systemic inflammation have recently been identified as a powerful predictors of cardiovascular risk both in the non-dialysis patient population and in our patients as well. Oxidative stress and chronic inflammation has emerged has an important cofactor for the development of endothelial dysfunction and atherogenesis (72). A recent seminal study by Stenvinkel et al (31) supports the concept that inflammation and nutrition may be key factors in the development of atherosclerosis. In this study, malnourished dialysis patients as assessed by SGA or patients with elevated CRP levels have significantly more carotid plaques compared to well-nourished dialysis patients or those with normal CRP levels. Multivariate analysis noted that CRP and vitamin E levels were the factors that were most significantly associated with increased carotid intima-media area. They concluded that the accelerated atherosclerosis in patients with chronic renal failure appears to be caused by a synergism of different mechanisms, including malnutrition, inflammation, oxidative stress and genetic components.

Don F2a

Fig. 1 - CRP (a positive acute-phase protein) and PCRn (a nutritional parameter) independently predict hypoalbuminemia in hemodialysis patients.

Sources of Inflammation

One potential source of inflammation in dialysis patients is exposure of circulating mononuclear cells to the dialysis membrane, or potential exposure of circulating blood to lipopolysaccharide (LPS) on the dialysate side of the membrane. Bio-incompatible membranes such as cuprophane, activate white cells (73), complement (74), and can even exert effects on residual renal function (75). Activation of cytokines has also been found to occur following dialysis with cuprophane (76) in contrast to biocompatible membranes (77,78). Reuse technique and numbers of reuse also may contribute to the interaction of blood with dialyzer (34,35) leading to changes in protein loss, and possible changes in the acute phase response. Pyrogenic reactions in the absence of septicemia is closely associated with reuse (79).
A very rapid and similar increase in IL -Iß and the acute phase protein SAA was seen during 240 minutes of dialysis with cuprophane, cellulose acetate and polymethylmethachrylate (80), the latter two being biocompatible membranes. Cytokine production has been demonstrated during in vitro dialysis of whole blood (81), suggesting that interaction of circulating nuclear cells directly stimulates cytokine production. Dialysis also alters mononuclear cells so as to make them respond more vigorously to subsequent exposure to endotoxin (82).
Not all laboratories have been able to replicate these findings using biocompatible membranes. We were unable to find any increase in expression for genes encoding several cytokines in circulating mononuclear cells collected from a small number of hemodialysis patients with high CRP levels (34), and others also have not been able to identify circulating mononuclear cells as a potential source for stimulating inflammation in hemodialysis patients (83). We also found no consistent change in SAA when the level of this protein was measured in 113 hemodialysis patients. There was also no relationship between reuse number and the change in SAA value (34).
There has been recent interest in the role that advanced glycosylation end-products (AGEs) may have in causing oxidative stress and inflammation in patients with end-stage renal disease (84). Normally, reducing sugars such as glucose react nonenzymatically and reversibly with free amino groups in proteins to form small amounts of stable Amadori products through Schiff base adducts. This process, with eventual spontaneous irreversible modification of proteins by glucose, results in the formation of AGEs, a heterogeneous family of biologically and chemically reactive compounds with crosslinking properties. This process of protein modification is magnified by the high ambient glucose concentration present in diabetes, and AGEs accumulate in proportion to the decrease in glomerular filtration rate in patients with renal failure (84). Pentosidine and carboxymethylysine are useful markers of AGEs and are elevated in both plasma proteins and skin collagen of uremic patients, regardless of the presence of diabetes (85). Moreover, dialysis has no significant effect on lowering these levels. Recent studies by Miyata et al (86) have suggested that a high oxidative stress associated with uremia is responsible for the formation of AGEs. This increased oxidative stress also extends to cause irreversible lipoxidation resulting in the formation advanced lipoxidation end-products. AGEs and lipoxidation end-products increase vascular permeability, augment coagulation and monocyte migration, and IL-6 production by monocytes. AGEs appear to participate in a vicious cycle of oxidation/inflammation in that the formation of AGEs is promoted by oxidative stress and AGEs can induced oxidative stress in cells bearing AGE receptors (87).
Another issue of significance is the variability of the levels of both cytokines and acute- phase proteins over time. As noted earlier, cross-sectional studies have found a strong correlation between CRP and albumin concentration (34, 84), and between CRP (64) and IL-6 (61) and mortality. These measurements are made at one point in time. In a recent longitudinal study in 37 hemodialysis patients we found that the acute phase proteins, CRP and *₁ acid glycoprotein, varied significantly over time with no change in dialyzer type or treatment, suggesting that non-dialysis related processes might be responsible for altered expression of the acute phase response in these patients (89). The variances in CRP was an order of magnitude greater than that for albumin or transferrin. Clearly this variability in inflammation over time was unlikely to be related to dialysis, since that process did not change over time. By far, the most powerful predictor for a change in serum albumin concentration in this study, was a change in the level of CRP. The protein catabolic rate, which is a proxy for steady state dietary protein intake, had a much smaller predictive effect on changes in albumin concentration. Similar to the cross-sectional studies, the effect of changes in protein catabolic rate on changes in serum albumin levels were independent of CRP levels in this longitudinal study. Thus two independent processes, inflammation and reduced protein catabolism, most likely reflecting reduced protein intake, each separately contribute to causing a decrease in serum albumin concentration.
The systemic inflammatory response in dialysis patients may be a consequence of unrecognized clinical infection (90). This possibility must be excluded in any dialysis patient who develops hypoalbuminemia. Dialysis patients are immune suppressed (91,92). They have increased incidence of tuberculosis (93) and access site infections (94-96). The latter is at least in part determined by the type of vascular access (graft vs. fistula) and the number of graft revisions. Both were associated independently with permanent access-site infection (94). These infections may lead to metastatic infection elsewhere (97). In our own study we found that serum albumin concentration was lowest in patients having transcutaneous access (34) and CRP twice as great when compared to patients having arteriovenous (AV) fistulas. Patients with AV grafts were intermediate. These differences may have been a consequence of unrecognized infection in the AV grafts. A recent study by Ayus et al (98) highlights this issue by demonstrating that one can no longer ignore clotted non-functioning grafts inasmuch as they may harbor silent infection. They performed indium-labeled WBC scans in 20 dialysis patients with thrombosed non-functional grafts with fever, and/or sepsis but without localizing signs, and 21 asymptomatic control patients with older clotted grafts. The indium scans showed uptake in the graft in all patients with clinical infection and in 15 control patients. Removal of the grafts revealed infected clot, most commonly containing Staphylococcus aureus or Staphylococcus epidermidis, in all symptomatic patients and in 13 of the 15 controls with positive scans. Thus, silent infection in non-functioning, innocent appearing grafts may be one of the unrecognized causes of systemic inflammation in dialysis patients. In fact, this concept has been supported by an another prelimary study by Fishbane et al (99) in which they studied 20 patients with elevated CRP levels, low serum albumin concentrations and evidence of erthyropoietin resistance. Eight of the twenty patients had non-functioning grafts and of these, indium scans were positive in six. Five of the six patients had resection of the non-functioning grafts, which revealed evidence of purulent material, and the patients were treated with antibiotics. What is provocative about this pilot study is that two months after removal of the grafts, CRP levels and erthyropoietin resistance significantly decreased suggesting that the initial elevations were due to unrecognized infection in old non-functioning grafts.

Don F2a

Fig. 2 - See text for details.

Inflammation and Nutrition: The Link?

There is a complex relationship between inflammation, cytokines and nutritional status. Inflammation, through mechanisms mediated by cytokines, causes muscle and fat mass to decrease and alters serum protein composition in a manner similar to that encountered in protein calorie malnutrition (100, 101). Cytokines suppress appetite, possibly by augmenting leptin gene expression (102). A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective utilization of dietary protein and energy intake. In addition, augmented catabolism increases the patient's protein requirements that cannot be met given the impairment in protein-caloric intake in the anorectic dialysis patient. The result is the wasting syndrome of chronic renal failure. Even in the absence of reduced caloric intake, inflammation increases tissue catabolism in part by acting through a ubiquitin-mediated pathway (103). It is interesting to note that the synthesis of postive acute-phase reactive proteins, is also impeded by protein malnutrition (104, 105) even following an appropriate inflammatory stimulus. Thus the absence of an increase in the plasma levels of positive acute-phase reactive proteins does not itself prove that albumin synthesis is not in part inhibited as a component of the inflammatory response: inflammation may still be present in a patient with hypoalbuminemia who fails to increase plasma levels of positive acute- phase proteins if malnutrition is severe enough. Cytokine release, however, still occurs in protein calorie malnourished states (106), although the magnitude of release may be diminished. Inflammation closely mimics the effects of malnutrition on the concentration of negative acute-phase proteins in plasma and in body morphometry, and indeed can lead to malnutrition by promoting anorexia.
As we better understand the role of systemic inflammation and poor protein-caloric intake as a cause for increased morbidity and mortality, the clinician is faced with the challenge of how best to treat these insidious processes. The National Kidney Foundation (USA)-Dialysis Outcomes Quality Initiative (DOQI) group are currently developing nutritional guidelines for the practicing clinician. Although few nutritional interventions have been well studied to determine whether they may be effective, providing nutritional supplements or using intradialytic parenteral nutrition may improve serum albumin levels and possibly survival (107). The more difficult situation is how to recognize and treat the patient with systemic inflammation. The assay for CRP is an automated, inexpensive and reliable assay, and should be used routinely in evaluation of these patients, especially when hypoalbuminemia is present. The next problem, as noted earlier, is the difficulty in pin-pointing the cause or causes for initiation of inflammation (i.e. occult infection, dialyzer issues etc.) The clinician can recognize the biochemical features of systemic inflammation in their patients (i.e. increased CRP level, decreased albumin), but etiology of this process is often elusive. The third problem is how do we circumvent the inflammatory cascade and its untoward effect on our patient's metabolism and ultimate survival. Designing new therapeutic strategies will be the challenge and these may include the use of anabolic therapies such as growth hormone, androgens, and insulin-like growth factor-1, anti-catabolic agents such as thalidomide and IL-receptor antagonists, and appetite stimulants such as megestrol and marijuana.

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.

Reprint requests to: Burl R. Don, M.D. - Division of Nephrology University of California Davis Medical Center 4150 V Street, Suite 3500 Sacramento CA, USA br.don@ucdmc.ucdavis.edu

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Received: December 23, 1999 Revised: February 16, 2000 Accepted: April 05, 2000

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