Approaches to uremia

Abstract

The development of dialysis was a dramatic step forward in medicine, allowing people who would soon have died because of lack of kidney function to remain alive for years. We have since found, however, that the "artificial kidney" does not live up fully to its name. Dialysis keeps patients alive but not well. Part of the residual illness that dialysis patients experience is caused by retained waste solutes that dialysis does not remove as well as native kidney function does. New means are available to identify these toxic solutes, about which we currently know remarkably little, and knowledge of these solutes would help us to improve therapy. This review summarizes our current knowledge of toxic solutes and highlights methods being explored to identify additional toxic solutes and to enhance the clearance of these solutes to improve patient outcomes.

Keywords: chronic dialysis; urea; uremia.

Figure 1.

The predicted pretreatment solute level in patients receiving conventional thrice-weekly hemodialysis relative to the level in healthy persons ([X]_HD-APC/[X]_NL) is plotted on the vertical axis. The ratio varies widely among solutes depending on the ratio of the dialytic clearance to normal kidney clearance (K_D/K_NL) and on the concentration reduction ratio during treatment, defined as the pre- minus post-treatment concentration divided by the pretreatment concentration. Because the ratio of dialytic clearance to normal kidney clearance for urea is very high, its average pretreatment level remains <10-fold normal. The ratio of dialytic clearance to normal clearance is lower for other solutes, and their plasma levels therefore rise higher. This is particularly the case for solutes that are secreted by the native kidney, and levels of some of these solutes, including free, unbound indoxyl sulfate, remain >100-fold normal in patients receiving conventional treatment. Their high plasma levels are a predictable consequence of replacing the native kidney's secretory function by a treatment that clears solutes by diffusion. The figure is reproduced from Sirich et al., which further describes the modeling procedure and measured values for solute levels.

Figure 2.

The predicted effect of increases in time-averaged clearance on plasma levels of different types of solutes. In each panel, solute levels are normalized and the pretreatment level obtained with the lower time-averaged clearance is assigned a value of 100. The left panel depicts the effect of increasing Kt/V_urea on levels of urea. The red line depicts levels obtained with a conventional dialysis prescription designed to achieve spKt/V_urea of 1.4 during dialysis sessions lasting 3.5 hours. The blue line depicts the predicted effect on urea levels of increasing the urea clearance by 15% and the session length to 4 hours so that spKt/V_urea is increased by close to 30%. This increase is similar in magnitude to that achieved in the “high dose” group of the HEMO study, and its effect is to reduce time-averaged urea levels by 15%–20%. The middle panel depicts the effect of the same two prescriptions on levels of a hypothetical small, unbound solute that is distributed only in the extracellular fluid. Because the clearance is high relative to the volume of distribution, the conventional prescription removes the solute almost completely. The increases in session length and clearance, which together provide a 30% higher “dose” of dialysis as measured by Kt/V_urea, reduce the time-averaged solute concentration by <10% (blue line). The right panel depicts the predicted effect on β₂-microglobulin levels of increasing β₂-microglobulin's dialytic clearance from 3.4 ml/min to 34 ml/min during dialysis sessions lasting 3.5 hours. This 10-fold increase was the difference between the “high flux” and “low flux” groups of the HEMO Study. The large increase in clearance resulted in a much smaller relative decrease in β₂-microglobulin levels, due largely to the presence of nonrenal, nondialytic β₂-microglobulin clearance, and average β₂-microglobulin levels remained >20-fold normal. Adapted from reference with added calculations based on reference ; additional discussion of the kinetics of solutes other than urea is provided in references and .