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      Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients

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          Abstract

          Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine’s. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO’s high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

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

            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.
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              Impact of increasing haemodialysis frequency versus haemodialysis duration on removal of urea and guanidino compounds: a kinetic analysis.

              Patients with renal failure retain a large variety of uraemic solutes, characterized by different kinetic behaviour. It is not entirely clear what the impact is of increasing dialysis frequency and/or duration on removal efficiency, nor whether this impact is the same for all types of solutes. This study was based on two-compartmental kinetic data obtained in stable haemodialysis patients (n = 7) for urea, creatinine (CREA), guanidinosuccinic acid (GSA) and methylguanidine (MG). For each individual patient, mathematical simulations were performed for different dialysis schedules, varying in frequency, duration and intensity. For each dialysis schedule, plasmatic and extraplasmatic weekly time-averaged concentrations (TAC) were calculated, as well as their %difference to weekly TAC of the reference dialysis schedule (three times weekly 4 h). Increasing dialysis duration was most beneficial for CREA and MG, which are distributed in a larger volume (54.0 +/- 5.9 L and 102.6 +/- 33.9 L) than urea (42.7 +/- 6.0 L) [plasmatic weekly TAC decrease of 31.5 +/- 3.2% and 31.8 +/- 3.8% for CREA and MG with Q(B) of 200 mL/min, compared to 25.7 +/- 3.2% for urea (P = 0.001 and P 65% for all solutes. Comparable results were found in the extraplasmatic compartment. Prolonged dialysis significantly reduces solute concentration levels, especially for those solutes that are distributed in a larger volume. Increasing both dialysis frequency and duration is the superior dialysis schedule.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 December 2015
                2015
                : 10
                : 12
                Affiliations
                [1 ]Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
                [2 ]Department of Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America
                Medical University of Graz, AUSTRIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: THH TWM PD MAD. Performed the experiments: XH VL. Analyzed the data: THH TWM XH MAD. Wrote the paper: THH TWM MAD.

                Article
                PONE-D-15-21399
                10.1371/journal.pone.0143731
                4674074
                26650937

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                Page count
                Figures: 0, Tables: 1, Pages: 7
                Product
                Funding
                This study was supported by the National Institutes of Health RO1 DK 080123, THH and TWM; American Heart Association FTF 15920005, MAD; Rosenberg Foundation of the Centers for Dialysis Care, THH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                All relevant data are within the paper and its Supporting Information files.

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