Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome

Abstract

Protein-bound uremic toxins (PBUTs) are predominantly excreted by renal tubular secretion and hardly removed by traditional hemodialysis (HD). Accumulation of PBUTs is proposed to contribute to the increased morbidity and mortality of patients with end-stage kidney disease (ESKD). Preserved PBUT excretion in patients with residual kidney function (RKF) and/or increased PBUT clearance with improved dialysis techniques might improve the prognosis of patients with ESKD. The aims of this study are to explore determinants of PBUTs in HD patients, and investigate whether hemodiafiltration (HDF) lowers PBUT plasma concentrations, and whether PBUTs are related to the outcome. Predialysis total plasma concentrations of kynurenine, kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl sulfate, p-cresyl glucuronide, and hippuric acid were measured by UHPLC-MS at baseline and after 6 months of follow-up in the first 80 patients participating in the CONvective TRAnsport Study (CONTRAST), a randomized controlled trial that compared the effects of online HDF versus low-flux HD on all-cause mortality and new cardiovascular events. RKF was inversely related to kynurenic acid (p < 0.001), indoxyl sulfate (p = 0.001), indole-3-acetic acid (p = 0.024), p-cresyl glucuronide (p = 0.004) and hippuric acid (p < 0.001) plasma concentrations. Only indoxyl sulfate decreased by 8.0% (−15.3 to 34.6) in patients treated with HDF and increased by 11.9% (−15.4 to 31.9) in HD patients after 6 months of follow-up (HDF vs. HD: p = 0.045). No independent associations were found between PBUT plasma concentrations and either risk of all-cause mortality or new cardiovascular events. In summary, in the current population, RKF is an important determinant of PBUT plasma concentrations in HD patients. The addition of convective transport did not consistently decrease PBUT plasma concentrations and no relation was found between PBUTs and cardiovascular endpoints.

Differences in Gut Microbiota Profiles and Functions Between End-stage Renal Disease and Healthy Populations 

“…Similar nding reporting a positive correlation between urea levels (represent the protein intake) and microbiota diversity supports this claim [32]. Furthermore, a high-protein intake increases the plasma levels of protein-bound uremic toxins and urea in healthy individuals [33] and ESRD patients [34]. Thus, high-protein intake may increase gut microbiota diversity.…”

Inverted U-Curve Association between Serum Indoxyl Sulfate Levels and Cardiovascular Events in Patients on Chronic Hemodialysis

“…However, a post-hoc analysis of the HEMO trial, which recruited 1273 participants with a median observation time of 2.3 years, failed to demonstrate a linear association between serum levels of PCS and IS and cardiovascular outcomes in dialysis patients [ 18 ]. Moreover, a study by van Gelder MK et al with 80 participants with dialysis who were followed for a median time of 4.3 years showed that the continuous forms of serum IS and PCS had no significant associations with all-cause mortality and CV events [ 17 ]. Therefore, the PBUTs seem to have no significantly linear association with CV events in dialysis patients.…”

“…However, previous studies have reported neutral findings regarding the relationship between PBUTs and clinical outcomes, including all-cause mortality and CV events in patients with CHD [ 17 , 18 ]. A reverse epidemiology finding linked to protein–energy wasting in dialysis patients has been reported [ 19 , 20 ].…”

How do Uremic Toxins Affect the Endothelium?

“…Evidences indicates that HDF is superior to conventional hemodialysis therapy for recovery of endothelial function, likely due to a broader clearance of uremic toxins [ 186 , 187 ]. Despite of similar removal of protein-bound uremic toxins, HDF provides superior removal of low-molecular weight protein when compared to high-flux-hemodialysis [ 188 , 189 ]. Among the three main options for convective dialysis therapies, post-dilution HDF has been reported to be more effective than pre-dilution HDF and pre-dilution hemofiltration for the removal of uremic toxins [ 190 ].…”

“…Finally, as uremic toxins levels has been related to residual kidney function in dialysis patients [ 189 , 194 ], its preservation is ultimately an important therapeutic approach for a better control of uremic toxins levels. Even though these results are promising, they should be interpreted with caution.…”