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Thursday, 13. February 2003 12:20 PM GMT
Adequacy of dialysis refers to the compromise between therapeutic outcome &
cost & inconvenience.
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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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,
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 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 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).
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 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).
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)
5-Hydroxyindol acetic acid