Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular secretion

Abstract

Dialytic clearance of urea is efficient, but other small solutes normally secreted by the kidney may be cleared less efficiently. This study tested whether the high concentrations of these solutes in hemodialysis patients reflect a failure of passive diffusion methods to duplicate the efficacy of clearance by tubular secretion. We compared the plasma concentrations and clearance rates of four solutes normally cleared by tubular secretion with the plasma concentrations and clearance rates of urea and creatinine in patients receiving maintenance hemodialysis and normal subjects. The predialysis concentrations (relative to normal subjects) of unbound phenylacetylglutamine (122-fold), hippurate (108-fold), indoxyl sulfate (116-fold), and p-cresol sulfate (41-fold) were much greater than the concentrations of urea (5-fold) and creatinine (13-fold). The dialytic clearance rates (relative to normal subjects) of unbound phenylacetylglutamine (0.37-fold), hippurate (0.16-fold), indoxyl sulfate (0.21-fold), and p-cresol sulfate (0.39-fold) were much lower than the rates of urea (4.2-fold) and creatinine (1.3-fold). Mathematical modeling showed that prominent accumulation of the normally secreted solutes in hemodialysis patients could be accounted for by lower dialytic clearance relative to physiologic clearance combined with the intermittency of treatment. Whether or not more efficient removal of normally secreted solutes improves outcomes in dialysis patients remains to be tested.

Figure 1.

Determinants of plasma solute accumulation in hemodialysis patients. Predicted pretreatment solute levels in patients maintained on conventional hemodialysis relative to those levels in normal subjects. The ratio of the average pretreatment solute concentration in hemodialysis patients to the concentration in normal subjects ([X]_HD-APC/[X]_NL) is plotted on the vertical axis as a function of the ratio of the dialytic clearance to normal clearance (K_D/K_NL) and concentration reduction ratio defined as the pre- minus post-treatment concentration divided by the pretreatment concentration. Values were calculated assuming that treatment is performed three times per week for 3.5 hours, that solute production is constant and the same in patients and normal subjects, and that solute is removed from a single compartment. If a solute's concentration does not fall much during treatment, intermittency does not diminish the efficiency of treatment, and the solute's concentration in dialysis patients relative to normal subjects approaches the normal clearance K_NL divided by the time-averaged dialytic clearance, which is obtained by multiplying K_D by the fraction of the week for which treatment is applied (here 10.5 hours/168 hours). As the reduction ratio increases, intermittency limits the effect of treatment, and therefore, the solute concentration ratio is higher for any given value of K_D/K_NL. The asterisks illustrate the model's prediction in accordance with measured values that, although conventional three times per week hemodialysis restricts the average pretreatment concentration of urea to less than 10-fold normal, leaves the average pretreatment concentration of free, unbound indoxyl sulfate greater than 100-fold normal. If a solute is modeled as being removed from a single compartment, the reduction ratio is determined by the ratio of the dialytic clearance to the volume of distribution, K_D/V_D. A low reduction ratio is equivalent to the assumption that the volume of distribution is large relative to the dialytic clearance. The ratio of the pretreatment solute concentration in hemodialysis patients to the concentration in normal subjects ([X]_HD-APC/[X]_NL) can, therefore, alternatively be plotted as a function of K_D/K_NL and K_D/V_D (Supplemental Figure 3). Modeled values for solute concentration are somewhat higher if it is assumed that dialysis removes solute from a first accessible compartment and solute moves by diffusion between this compartment and a second compartment. The pattern of concentration dependence on the ratio of dialytic to native kidney clearance and the reduction ratio, however, remains the same (Supplemental Figure 2).