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Thursday, 13. February 2003 12:20 PM GMT

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Uraemic toxicity & its role in adequacy of dialysis

The quest for adequate dialysis is overshadowed by the lack of definition of uremic toxicity. The attenuation of uremic symptoms by the restriction of dietary protein and by dialysis underscores the role of retention, removal and metabolism in the uremic syndrome, but our knowledge on pathophysiology remains fragmentary. The discussion of the uremic toxin is an oversimplification. Toxicity may result from the synergism of the entire spectrum of accumulated components. Many solutes exert in vitro effects, but their responsibility in vivo is more difficult to establish a specific removal eliminates essential compounds together with potential toxins. A more correct outline of the essentials of uremic toxicity is thus indispensable for delineating exactly how dialysis should be performed adequately. In the meantime we have to rely on indirect estimates, so-called markers (Vanholder and Ringoir, 1992).

Ideal marker of adequacy could be defined as: (1) retained in renal failure; (2) eliminated by dialysis; (3) with proven toxicity; (4) generation and elimination representative for other (preferably toxic) solutes; (5) concentration related to clinical outcome; (6) easily determined. No current marker matches with all these conditions (Vanholder and Ringoir, 1992).

Dialysis should reduce the concentrations of uraemic toxins to an acceptably low level. The measurement of dialysis adequacy then reduces to the simple matter of measuring the concentrations of uraemic toxins in the blood. Unfortunately, we have not yet approached this ideal. While a large number of uraemic toxins are known, their relative contribution to the uraemic state is not. Most known uraemic toxins are present in trace amounts, are difficult to measure and their toxicity may depend on complex interactions between them. Only the concentrations of beta-2-microglobulin and the hydrogen ion have been unequivocally linked to outcome and are sufficiently easy to measure to be suitable for routine monitoring (Tattersal et al., 1998).

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Small molecules:

Urea:

Urea is easy to measure and is present in high concentrations in the blood of uremic patients. Although it is relatively non-toxic, healthy kidneys remove far more urea than any other metabolite (5-10 mole/week). Urea clearance may be related to uremic toxicity by two possible mechanisms, toxicity may be related to the blood concentrations of uremic toxins. In this case, toxins may be cleared at a similar rate to urea but their generation rate, unlike that of urea, is constant and independent of diet so that blood concentrations increase as clearance declines. Alternatively, declining clearance may inhibit generation, adversely affecting nutritional and metabolic health independent of the blood concentration (Tattersal et. al., 1998).

Urea is the predominant nitrogen waste product of protein catabolism (Walser, 1980). Protein contains approximately 16% nitrogen by weight, and during protein catabolism virtually all of the nitrogen is converted to urea. Less than 19% of protein nitrogen is converted to substances other than urea, mainly creatinine and uric acid. In normal patients and in those with stable chronic renal failure, the level of (BUN) is known to vary directly with dietary protein intake (Mitch, 1989). Therefore, one can be able to assess protein intake in dialyzed chronic renal failure patients by monitoring changes in the body pool of urea. Net urea enters the body pool only as a result of the degradation of protein, either dietary or endogenous. This is the consequence of the fact that the enterahepatic recirculation of urea neither add to nor subtracts from the body pool of urea (Mitch, 1989).

All the urea that diffuses into the gut and is converted into ammonia by gut bacteria is quantitatively recovered by hepatic conversion of ammonia back to urea (Mitch et. al., 1977). Further more, there is no convincing evidence that patients with chronic renal failure utilize urea as a source of nitrogen for protein anabolism. Even if some urea is removed from the body pool for the production of protein, the amount is nutritionally small and quantitatively unimportant. Because of this quantitative recovery of degraded urea, a decrease in the body pool of urea is affected only through dialysis or residual renal clearance. Therefore, urea balance may be considered simply as the difference between protein catabolism and dialytic and residual renal clearance (Walser, 1980).

Traditionally, the pre-dialysis concentrations of urea and creatinine in the blood have been used as a surrogate for the concentrations of other uraemic toxins. This approach has now been discredited. The concentration of these solutes depends as much on their generation rate as on their clearance rate. Creatinine and urea generation rates are functions of muscle mass and protein catabolism respectively. One large study demonstrated a progressively increasing mortality rate as pre-dialysis urea and creatinine concentrations fell, reflecting malnutrition and, possibly underdialysis in those patients with low creatinine and urea concentrations (Lowrie and Lew, 1990).

Phosphorus:

Phosphorus concentration is the result of protein catabolism and protein intake, but also of extra dietary phosphate sources (assorted meat products, Cabbages, etc.). Intra-dialytic evolution is not straightforward and is not comparable to that of urea, creatinine or uric acid (Sugisaki et.al., 1982). Dialytic removal is followed by a marked rebound (Haas et.al., 1991 ), even during dialysis there is no direct correlation with urea elimination. As a marker, its behavior is too specific, and not directly representative for other compounds (Sugisaki et.al., 1982).

Middle molecules:

Middle molecules are intangible compounds with molecular weight between 300 and 5,000 Dalton (Schoots et.al., 1984),that may interfere with peripheral nerve function (Babb et.al., 1981), although well controlled toxicology studies are lacking. Middle molecular peaks are prominent in sever uremia (Furst et.al., 1976).The major problem was the lack of well defined representative solutes of middle molecular range. With improved analytic techniques, it became evident that presumed middle molecular fractions are in fact heterogeneous mixtures containing many lower molecular weight compounds (Schoots et.al., 1984), which extends the definition of middle molecules to the smaller molecules with protein binding and/or multicompartmental distribution. In at least 10 studies, reduction of urea elimination, coupled to an unchanged or enhanced "middle molecule" removal, caused no deterioration of clinical condition (Wizemann et.al. 1983). On this basis, Lindsay and Henderson recommended to choose a membrane that gives the highest clearances in the larger, as well as in the low molecular weight range (Lindsay and Henderson, 1988).

Large molecules:

B2 microglobulin:

B2 microglobulin (molecular weight 11.600 Dalton), a substantial amount is eliminated via residual renal function.B2 microglobulin distributes as an unbound monomer in two body water compartments, plasma and interstitial fluid (Vanholder and Ringoir, 1992).B2 microglobulin is one of the few well-documented uraemic toxins. It is related in the body as a result of normal cell turnover and is normally filtered at the glomerulous and metabolized in the renal tubules. The pore size of many dialysis membranes in common use (for example Cuprophane) is insufficient to clear any B2-microglobulin. Even if a high Kt/v is prescribed using long dialysis times, B2 microglobulin accumulates as amyloid in the patient. This form of amyloidosis affects the joints, producing a progressively disabling arthropathy after 5 to 10 years of dialysis, Death from amyloidosis of gut and heart may occur after 20 years of dialysis (Tattersal et. al., 1998).

Hippuric acid:

Hippuric acid behaves like a larger molecule, due to protein binding, that even increases during dialysis (Zimmerman et. al., 1990), it can easily be determined by colorimeteric methods as well as by high performance liquid chromatography (Vanholder et. al., 1988).

Parathormone:

Concentration of parathormone, a large molecule with proven toxicity results from a number of compensatory mechanisms, rather than accumulation, Elimination by dialysis is not critical except with some membranes, such as polyacrylonitrile that mainly adsorb parathormone. Serum parathormone is an indirect parameter of chronic inadequate dialysis since its production follows phosphate accumulation (D'Amour et.al., 1990).

Uraemic solutes with potential toxicity:

(Vanholder and Ringoir, 1992)

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