Nephrol Dial Transplant (2001) 16 wSuppl 6x: 111–113
Pathogenesis and management of malnutrition in chronic peritoneal dialysis patients N. V. Dombros Peritoneal Dialysis Unit, AHEPA University Hospital, Thessaloniki, Greece
Introduction Protein-energy malnutrition is common (18–55%) among dialysed uraemic patients w1,2x. A variety of factors may cause or contribute to the development of malnutrition in chronic renal failure (CRF), haemodialysis (HD), and peritoneal dialysis (PD) patients w3x. These include: (i) inadequate nutrient intake due to inadequate dialysis, dietary restrictions, old age, poverty, depression and suppressed appetite because of the increased intraperitoneal pressure, absorption of glucose from the dialysate, various medications, gastroparesis etc. (ii) Loss of proteins and amino acids from the peritoneum. On average, the daily loss of protein via the dialysate is in the order of 6–9 guday; however, there is a large inter-individual variation from 3 to 20 guday w4x. During or after peritonitis this quantity may be increased by 50–100%. Daily total amino acid losses average 2.5 g (range 1.2–3.4) w5x; and (iii) increased catabolism due to co-existing systemic diseases, infections such as peritonitis, chronic inflammation, underdialysis, metabolic acidosis or other hypercatabolic diseases w3x. In many PD patients many of these factors exist in combination. As a result, in only a few PD patients an increase in the recommended protein and energy intake is effective in controlling malnutrition.
Assessment of malnutrition So far, we do not have a single definite test by which to assess nutritional status in CRF patients. Therefore, a plethora of tests have been applied for that purpose. Nutritional assessment relies on medical history, physical examination, evaluation of nutrient intake, anthropometric measurements, biochemical monitoring, assessment of lean body mass and per cent body fat, and hand-grip strength. Newer methods include
Correspondence and offprint requests to: Nicholas V. Dombros, Peritoneal Dialysis Unit, AHEPA University Hospital, 32, Ethnikis Aminis Street, Thessaloniki 54636, Greece. #
bio-electrical impedance, dual-emission X-ray absorptiometry, nuclear magnetic resonance, computerized tomography, total body nitrogen, and total body potassium. Subjective global assessment is based on a history of weight loss and symptoms such as anorexia, nausea and vomiting and has been shown, in many studies, to be a simple and reliable method for assessing the nutritional status in uraemic, pre-dialysis, HD, and PD patients. Of all biochemical markers used to evaluate nutritional status, serum albumin, so far, is the most common. However, as shown in various reviews, serum albumin is, rather, a poor nutritional marker in healthy subjects, pre-dialysis and dialysis patients w6,7x. Serum albumin level is regulated by several factors, especially protein malnutrition, protein losses and inflammation. The latter can lead to a more marked hypoalbuminaemia than pure insufficient protein intake, because it suppresses albumin synthesis and causes transfer of albumin from the vascular to the extravascular space. Of course, the combination of malnutrition and inflammation will lead to a significant reduction in serum albumin concentration w7x.
The role of inflammation in malnutrition and atherosclerosis There are several causes of inflammation in uraemic patients. Causes related to chronic renal failure per se include: reduced renal clearance of cytokines, and advanced glycation products, congestive heart failure (CHF), the atherosclerotic process per se, various inflammatory diseases, as well as unrecognized persistent infections, e.g. Chlamydia pneumoniae, Helicobacter pylori, or dental anduor gingival infections. Additional causes in HD are: graft and fistula infections, bioincompatibility of artificial membranes and exposure to endotoxins and other cytokine-inducing substances from contaminated dialysate. Finally, additional causes of inflammation in PD patients include peritonitis, exitsite infection, bio-incompatibility of dialysis solutions and exposure to endotoxins, plasticizers, and other
2001 European Renal Association–European Dialysis and Transplant Association
cytokine-inducing substances from contaminated dialysate w8x. Recently, attention has been focused on the association of malnutrition, inflammation, and atherosclerosis (MIA syndrome) in CRF patients w7,11x. Chronic inflammation, is evidenced by increased levels of C-reactive protein (CRP) and other acute phase reactants, such as fibrinogen, serum amyloid, transferrin, serum albumin and pre-albumin, procalcitonin, and others. Major mediators of acute phase protein induction are various pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor-a (TNF-a) w7,9x. Dialysis patients have a high prevalence of increased both CRP and proinflammatory cytokines. An increased CRP level is a strong risk factor for cardiovascular (CV) mortality, hospitalization and hypoalbuminaemia in dialysis patients. High levels of pro-inflammatory cytokines may cause muscle wasting (by stimulating protein catabolism, reducing albumin synthesis, and inhibiting appetite) and muscle protein catabolism (by stimulating branched-chain ketoacid dehydrogenase, which leads to greater oxidation of branched-chained amino acids). As a result, increased plasma levels of pro-inflammatory cytokines predict hypoalbuminaemia and mortality in dialysis patients w7x. Although inflammation and hypoalbuminaemia predict mortality in dialysis patients, malnutrition per se accounts for -5% of deaths w12x, while atherosclerotic CV disease is very common in these patients. Available evidence suggests that the increased mortality rate observed in dialysis patients may be associated with inflammation rather than low serum albumin levels which often are caused by other mechanisms. Inflammation has been shown to be associated with endothelial dysfunction, insulin resistance and increased oxidative stress, all of which may accelerate atherosclerosis. Congestive heart failure is very common in PD patients and very often (50%) is accompanied by muscle wasting and elevated serum levels of TNF-a and IL-6 w7x. Altogether, nutritional and inflammatory markers are closely linked to CV disease and mortality in PD patients. Hence, it seems likely that elevated levels of pro-inflammatory cytokines could be the link between the high prevalence of malnutrition, inflammation and CV disease in these patients w7,8x. It has been suggested that there are two types of malnutrition in CRF patients w7,8x. Type-1 malnutrition (usually without co-morbidity) is characterized by the absence of inflammation, normalulow serum albumin, decreased protein catabolism, low food intake, normal resting energy expenditure, and increased oxidative stress. This type of malnutrition could be reversed by adequate dialysis and nutritional support. Type-2 malnutrition (associated with co-morbidity) is characterized by the presence of inflammation. This ‘cytokine-driven’ type of malnutrition has low serum albumin, increased protein catabolism, lowunormal food intake, elevated resting energy expenditure, markedly increased oxidative stress and resistance to
N. V. Dombros
increased dialysis, and nutritional support. In most PD patients these two types of malnutrition overlap. It is interesting that serum albumin concentration below 3.5 gudl is only found in type-2 malnutrition. Thus, in PD patients, hypoalbuminaemia most likely reflects the combination between malnutrition and inflammation. In addition to CRF patients, type-2 malnutrition is common among patients with CHF, rheumatoid arthritis, AIDS, advanced cancer and chronic respiratory insufficiency.
Management of malnutrition Standard treatment of malnutrition include measures such as early and adequate dialysis, nutritional counselling, nandrolone maleate, oral protein and amino acid supplements, enteral supplementation and intraperitoneal administration of amino acids. However, all these interventions cannot restore the normal nutritional status in all malnourished dialysis patients. In a recent analysis, it was found that data supporting the use of intradialytic parenteral nutrition in patients with CRF are weak w13x. Obviously, in some patients, inflammation plays a much more important role in the pathogenesis of malnutrition (type-2) than other non-inflammatory factors. Therefore, it becomes very important to identify these patients by measuring CRP, which is very simple. Patients with an elevated CRP anduor other acute phase reactants should receive appropriate attention and treatment for the management of chronic inflammation. New treatment strategies, based on the theory of MIA syndrome, include administration of angiotensin-converting enzyme inhibitors, which, not only improve cardiac function and reduce mortality, but also are shown to be associated with a better nutritional status and lower levels of TNF-a in chronic renal failure patients w14x. Vitamin C might be helpful in improving endothelial dysfunction, but should be avoided in doses )100 mguday, for fear of hyperoxalaemia. Antibacterial, and antiviral therapy will be most helpful, as they may improve both the cardiovascular and the nutritional status. Finally, anti-cytokine therapy, e.g. anti-TNF-a antibodies, soluble TNF-a receptors, IL-1 receptor antagonists and thalidomide (a TNF-a inhibitor), hold great promise for the near future w15x.
Conclusions Protein-energy malnutrition, common in CRF, contributes to the exceptionally high CV and total mortality of dialysed patients. Chronic inflammation, as evidenced by increased levels of pro-inflammatory cytokines and CRP, is also common in CRF patients and, through several pathogenetic mechanisms, may cause anduor aggravate pre-existing malnutrition and atherosclerotic CV disease, thus, contributing to the high mortality rate. Therefore, as, in malnourished
Pathogenesis and management of malnutrition in chronic PD patients
PD patients, an elevated CRP concentration indicates chronic inflammation, our efforts should focus on controlling the inflammatory state first. Only in the absence of inflammation, could a malnourished PD patient benefit from the traditional interventions, such as nutritional counselling, adequate dialysis, enteral or parenteral supplementation and intraperitoneal administration of amino acids.
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