The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes

Abstract

BackgroundThere is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable.We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS.MethodsWe tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment (“isohydric dialysis”). Eight stable hemodialysis patients underwent “isohydric dialysis” for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout.ResultsWe found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of “isohydric dialysis” (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound.The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid.ConclusionThese findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration (“isohydric dialysis:”), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.

Uremic Toxin Clearance and Cardiovascular Toxicities

“…Increasing dialysate flow and dialyzer size over a period of two weeks was shown to increase the dialytic clearances of IS and PCS but did not significantly reduce their plasma levels [ 65 ]. Other means of increasing the clearances of protein-bound solutes include the addition of a sorbent to dialysate and the addition to blood entering the dialyzer of substances, which displace bound solutes or reduce the binding capacity of albumin [ 78 , 79 , 80 , 81 ]. All of these methods have been shown to increase bound solute removal during in-vitro dialysis.…”

The renal transport of hippurate and protein‐bound solutes

“… The unbound fraction, measured in plasma ultrafiltrate, was derived from a prior study in subjects with ESRD (Etinger et al, ). As reported by Deltombe et al binding of hippurate averaged 34% in healthy controls and 39% in subjects with ESRD receiving hemodialysis (Deltombe et al, ).…”

Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury

“…The reduction in albumin concentration in patients with AKI would not by itself cause a notable reduction in solute binding unless the aggregate levels of bound solutes were causing competition for binding sites. Post-translational modifications of albumin and other changes in plasma composition, including pH, may contribute (19)(20)(21).…”