Page 695 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

682 SPECIAL THERAPY

UREMIA TOXINS, THE ROLE small-molecular-weight retention solutes that remain
49,82,120
OF UREA, AND ADEQUACY OF unidentified or unmeasured. Reduction of urea
appearance and the extrarenal removal of urea are used
HEMODIALYSIS to prescribe the therapy for uremia and to monitor the
efficiency and adequacy of these therapies. 50,76,172 This
Uremia retention solutes (uremia toxins) are broadly clas-
designation is both rational and problematic. Urea is
sified based on their physicochemical properties as small
uncharged, present at high concentration, readily
(water-soluble) solutes (MW, <500 Da), middle
detected, and readily diffused across all body fluid
molecules (>500 Da), and protein-bound solutes compartments and the dialysis membrane. As such,
(>15,000 Da). 178,179,180,182 The foundations for this
it serves as an excellent solute to document dialyzer per-
arbitrary classification have been based primarily on their
characteristics for dialytic removal. 182 The volume of formance and whole body clearance of low-molecular-
distribution of each of these substances further weight solutes. However, these unique features and its
determines its compartmentalization and accessibility minimal uremic toxicity question whether it appropriately
for dialytic removal. 23,97,178,182 Hundreds of solutes have or accurately reflects the dialytic behavior of other solutes
demonstrated intrinsic toxicity that mimics or reproduce with more profound uremic toxicity and thus may
68,180,181
overrepresent removal of these solutes.
particular aspects of the uremic syndrome, and thousands
Dietary protein intake directly influences the genera-
of retained solutes have now been demonstrated by mass
spectroscopy in uremic subjects. 133,177,182 Some retained tion rate (appearance) of urea, and dialytic clearance
and residual renal function influence its removal from
solutes, such as urea, have minimal inherent toxicity but
the body. Thus serum urea concentration is poised to
serve as markers for retention of similar but unidentified
solutes with greater clinical significance. 49,180 reflect renal function and dialytic and nutritional ade-
quacy. The individual contributions of urea generation,
Small water-soluble solutes have demonstrated signif-
icance in the expression of uremia because both the its removal, and its distribution volume to steady-state
serum urea concentration cannot be differentiated by
morbidity and mortality of uremia can be corrected by routine urea measurement; however, perturbations of
their removal with conventional dialysis. 179,182 Extensive
the steady-state induced by dialysis allow kinetic dissec-
prospective studies in human patients with kidney failure
tion of these independent parameters by formal urea
confirm significant outcome benefits associated with
kinetic analysis in patients undergoing hemodialysis
the extent of small-molecular-weight solute removal (Figure 29-1). 48,64,141 The kinetics of urea generation
(i.e., dialysis dose). 71,73,106,120,124 However, uremic
and removal have become the bellwether of the adequacy
toxicity is more complex than can be explained by reten-
assessment of dialysis delivery and nutritional status in
tion of small-molecular-weight solutes and attention 76
uremic subjects. The role of urea to function as a global
has refocused on retention of middle molecules and
protein-bound solutes that are poorly removed by surrogate for uremic toxicity remains controversial in
dialysis. 74,77,133,177,182 light of the broader recognition and assessment of middle
There is an empirical link between the appearance of molecules and protein-bound solutes as retained uremia
uremic signs and the accumulation of nitrogenous end- solutes. Similarly, urea assessment provides an incomplete
products of protein (amino acid) oxidation. Urea is a appraisal of dialysis delivery despite its documented utility
and evidence as a predictor of dialysis adequacy. Never-
small-molecular-weight (60 Da) nitrogenous metabolite
theless, the clinical assessment of urea and urea kinetic
whose plasma concentration exceeds that of all other ure-
modeling remain the recommended and established
mic solutes. It contributes minimally to the clinical
manifestations of uremia 86 but has remained fundamen- indices for determining adequacy and delivery of
73,76,82,106,120
therapeutic hemodialysis.
tally associated with the morbidity and outcome of ure-
A variety of manipulation and mathematical models
mic syndrome because of its abundance and its link to have been developed to characterize the kinetics of urea
the metabolism of dietary and endogenous nitrogen. 49,64 during dialysis and its relationship to adequacy.* Of these,
No single retention solute (including urea) has been the fractional clearance of the urea distribution volume
shown to explain the major consequences of the uremic
(Kt/V) has become the standard measure for the dose
syndrome. Azotemia must be viewed as a marker for 76
of dialysis delivered during a dialysis session. From
the collective appearance of numerous small water soluble
the same analysis, the generation rate of urea (G) can
compounds, protein carbamylation, redirected metabolic
be derived to estimate the protein catabolic rate (PCR)
pathways, or other small-molecular-weight solutes cou-
of the patient as a measure of the adequacy of dietary pro-
pled to nitrogen metabolism and/or bound to body
tein intake, and the volume of distribution of urea (V) can
proteins.
be computed to better define hydration and adjustment
The proven correlation of urea removal by hemodialy-
to the dose (Figure 29-1).
sis with outcome in renal failure has prompted the
designation of urea as a surrogate index for all putative
*References 47, 48, 64, 141, 153, 162, 172.