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.
Highlights
The kidney has two mechanisms to excrete uremic toxins into the urine
Plasma concentrations of the protein-bound uremic toxins (PBUTs) measured in our study population were higher than in the healthy population as reported in the literature, especially for the strongly protein bound toxins (Table 6) due to impaired tubular secretion and limited removal during HD, since only the free fraction is available for diffusion across the dialysis membrane
We found an association between normalized protein nitrogen appearance (nPNA), a measure of dietary protein intake, and kynurenic acid and indoxyl sulfate
Summary
The kidney has two mechanisms to excrete uremic toxins into the urine. Small water-soluble solutes (e.g., urea) are primarily eliminated by glomerular filtration and protein-bound uremic toxins (PBUTs) primarily by tubular secretion mediated by transporters, including organic anion transporters (OAT) and organic cation transporters (OCT) for removal of PBUTs [1,2,3]. Hemodialysis (HD) is a life-sustaining renal replacement therapy that partially replaces renal glomerular filtration, but not renal tubular function The latter may contribute to the high morbidity and mortality in dialysis patients. It is of note that residual kidney function (RKF) has been associated with improved survival in dialysis patients, possibly via preserved PBUT clearance [7,8,9]. These findings drawn attention to PBUTs as a potential target for removal by renal replacement therapy
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