The best starting point in an assessment of nutritional status is the careful physical examination. Features that may be suggestive of PEW include wasting of the temporalis, interosseous, quadriceps, or deltoid muscle groups and loss of subcutaneous fat. While the presence of edema may be suggestive of protein malnutrition in the general population, it cannot be relied upon in patients with end-stage renal disease (ESRD) who frequently have extracellular fluid volume expansion that is unrelated to their nutritional status.

The subjective global assessment (SGA) is a clinical tool that incorporates information elicited from the patient’s history (weight change, dietary intake, gastrointestinal symptoms, and functional impairment) as well as a physical examination. This information is then scored and patients are divided into one of 3 categories: well nourished, mild/moderate malnutrition, or severe malnutrition. While SGA can be used to distinguish severe malnutrition from normal nutrition, it is neither a sensitive nor reliable predictor of the degree of malnutrition.

Anthropometric measures are among the simplest methods of assessing nutritional status. These include weight, the calculated body mass index (BMI), mid-arm circumference, and skinfold thickness. While easy to measure, these indices are relatively insensitive to changes in body composition; they may be helpful when used in conjunction with other tests.

Serum albumin is the most frequently used measure of nutrition in patients with chronic kidney disease (CKD) or ESRD. Advantages of using serum albumin include its ease of measurement and low cost. The primary limitation is that albumin is a negative acute phase reactant, so albumin decreases in response to inflammation. Consequently, a low albumin cannot reliably distinguish signs of PEW from inflammation. Even a normal albumin level cannot be taken as a sign of adequate nutrition, because a normal albumin has been reported in patients with marked malnutrition in association with eating disorders.

Prealbumin is the precursor of the more abundant plasma protein, albumin. It has a shorter half-life and hence, is a more sensitive measure of changes in visceral protein stores compared with albumin. Despite this potential benefit, prealbumin levels are subject to the same changes in response to inflammation as is albumin, and the cost of a prealbumin assay is higher.

Bioelectrical impedance analysis (BIA) is a technique used to determine body composition by providing an estimate of total body water and can then be used to estimate lean body mass and fat mass. While the device is easy to use, it is not readily available in all PD units, and its use requires a trained operator. For the BIA to be accurate, a patient must be edema-free, a state that is not always present in patients undergoing dialysis. In addition, the estimates of lean body mass are based on comparisons of the BIA of the patient undergoing PD with estimates made in healthy individuals. The estimates should be compared with those made in well-nourished patients undergoing PD.

Ingested proteins are metabolized to several nitrogenous products, the principal one being urea. As a result, the normalized
protein equivalent of total nitrogen appearance (nPNA) can be calculated from the urea appearance rate. The utility of the nPNA is that in a metabolically stable patient, it is an accurate reflection of the dietary protein. There are several important concerns with the use of nPNA in the assessment of nutritional status. While the information provided by the nPNA is helpful, dietary protein intake is only one component of nutritional status. Furthermore, factors other than dietary protein intake may influence the generation of urea. For example, a catabolic patient will have increased urea generation resulting in an overestimation of dietary protein. The process of normalizing the PNA to body weight is of concern because the nPNA is lowest in well nourished or obese patients.

Despite the limitations associated with each of these markers, their use (either in isolation or in combination) can give the clinician a general sense of the nutritional status in the patient undergoing PD. Unfortunately, the lack of a criterion standard has limited our ability to identify malnutrition with certainty and to quantitate its severity in patients with ESRD.

One of the most important contributors to inadequate nutrition is the constellation of abnormalities present in uremia. As GFR declines, uremic toxins accumulate, leading to symptoms of nausea and diminished appetite. This is particularly evident in terms of dietary protein because it can decline in patients with advancing CKD. While there are likely several mediators of the anorexia seen in advanced CKD and ESRD, increased levels of the anorexigenic hormone, leptin, may play an important role. Uremic symptoms and decreased protein intake can lead to PEW. The corollary is that providing “adequate” solute clearance will ameliorate these symptoms. While there may be incremental benefit associated with increasing dialysis dose, there is likely a threshold above which increased clearance does not provide added nutritional benefit (as shown in ADEMEX study of patients undergoing PD). The effect of uremia on appetite is, therefore, most relevant among predialysis patients and dialysis patients who are being under dialyzed.

Concomitant with increasing levels of uremic toxins, patients with advancing CKD frequently develop metabolic acidosis. This acidosis is because of a combination of impaired ammoniagenesis and the accumulation of dietary sulfates and phosphates. Based on several animal and human studies, it has become clear that acidosis leads to protein catabolism and results in negative nitrogen balance. A major mediator of this protein catabolic effect is the ubiquitin-proteasome proteolytic pathway. If not corrected,
metabolic acidosis will contribute to malnutrition in predialysis patients. Once dialysis is initiated, however, the high concentration of lactate or bicarbonate in the dialysate usually resolves the acidosis, and it should not be a major factor in most patients with apparent PEW once PD has been initiated. One group of patients receiving dialysis who may be at risk of persistent metabolic acidosis is the group taking sevelamer HCl as a phosphate binder; in this case, the use of the carbonate form of sevelamer may avoid this problem.

Independent of the protein catabolism caused by metabolic acidosis, patients receiving dialysis appear to have chronic catabolism. While the basis for the increased protein breakdown present in patients with uremia is not fully understood, a major mechanism is resistance to anabolic hormones such as insulin and insulin-like growth factor 1 (IGF-1). This may explain why protein catabolism is further accelerated among diabetic patients receiving dialysis, who are known to have a high degree of insulin resistance.

Another important mechanism for protein catabolism in ESRD is chronic inflammation. The basis for inflammation is often multifactorial and may involve uremia per se, infection, periodontal disease, bioincompatibility of dialysis solutions, as well as genetic factors. The result of chronic inflammation is the release of proinflammatory cytokines. One such proinflammatory cytokine that has been implicated is tumor necrosis factor-alpha (TNF-α), which can induce NF-kappa B activation, promoting skeletal muscle wasting via the ubiquitin-proteasome proteolytic system. Proinflammatory cytokines such as TNF-α have also been shown to suppress appetite, possibly by increasing leptin production. While malnutrition and inflammation frequently coexist in certain disease states, the above data suggest that inflammation may also be causally linked to the PEW found in some patients with kidney disease.

Advanced CKD and ESRD also impose a major psychological burden on patients. Some patients experience depressive symptoms or a sense of apathy. These feelings can contribute to decreased appetite and a decline in nutritional status.

In addition to the above issues, dietary management of patients with advanced CKD and ESRD can be challenging because of hyperphosphatemia. Unfortunately, foods that are high in phosphorus are often excellent sources of protein, and caution is required when advising these patients about dietary restrictions that improve phosphate control because it may come at the expense of excessive protein restriction.

As a renal replacement modality, PD takes advantage of the fact that the peritoneum provides an excellent membrane for diffusive and convective clearance. The instillation of fluid into the peritoneal cavity may, however, contribute to PEW in some patients through several mechanisms.

Firstly, while the movement of uremic toxins and potassium down a concentration gradient from the peritoneal capillaries into the dialysate is advantageous, the movement of protein and amino acids in the same direction is not. It is known that protein
losses into the peritoneal dialysate can be quite variable. In one study, protein losses ranged from 3.5 to 13.2 g/day and unless protein intake at least matches protein losses, patients undergoing PD will be prone to a chronic state of negative protein balance in a manner that is similar to the nephrotic syndrome. Some of the variability in the degree of protein loss relates to peritoneal transport status, with rapid transporters losing more protein compared with slow transporters. Certain factors increase protein losses above a patient’s usual baseline rate; peritonitis causes peritoneal capillaries to become “leaky” and with prolonged peritoneal inflammation, the protein lost and the cytokines released can have an important adverse impact on nutritional status. Another cause of protein losses in the effluent is ascites. Protein loss in patients with ascites may exceed 30 g/day in the weeks after PD initiation; there are data suggesting that the amount of losses diminishes over time. When initiating PD in a patient with ascites, careful attention must be paid to the risk of protein malnutrition.

The instillation of fluid into the peritoneal cavity may have other adverse effects. It is known that intraperitoneal pressure rises when a patient has dialysate in their peritoneum, and that the increase in pressure is related to the size of the patient, the volume of fluid instilled, and the position of the patient. This increased intra-abdominal pressure may lead to symptoms of early satiety and consequent reduced dietary intake. This hypothesis is supported by results of two small studies in which gastric emptying was significantly slower in patients with dialysate in the abdomen compared to those with an empty abdomen. The most extreme delays in gastric emptying occurred in those with small body surface area. Delayed emptying may be most noticeable in diabetic patients undergoing PD who frequently have preexisting gastroparesis.

An additional risk factor for PEW relates to the primary constituent of the PD fluid being instilled. Most patients undergoing PD are dialyzed with dextrose-based solutions that contain concentrations of dextrose ranging from 76 mmol/L for a 1.5% dextrose solution to 215 mmol/L for a 4.25% dextrose solution. A high dextrose concentration in the peritoneum leads to net absorption of dextrose, and the amount of dextrose absorbed will vary widely, depending on the dextrose concentration, the time that the fluid is left to dwell, and the peritoneal transport status (rapid transporters absorbing the most). This is relevant because the caloric load from a single dextrose exchange ranges from approximately 50 to 300 kcal. This high carbohydrate load can reduce the appetite and hence the consumption of foods rich in protein and other nutrients.