Selectively increasing the clearance of protein-bound uremic solutes
01 Apr 2012-Nephrology Dialysis Transplantation (Oxford University Press)-Vol. 27, Iss: 4, pp 1574-1579
TL;DR: The removal of bound solutes can be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/V(urea) during extended treatment.
Abstract: Background. The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis.
Methods. Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min.
Results. Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27 ± 9 versus 14 ± 6 mL/min) and indoxyl sulfate (IS: 26 ± 8 versus 14 ± 5 mL/min) without altering the clearance of urea (204 ± 20 versus 193 ± 16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375 ± 200 versus 207 ± 86 mg/session; IS: 201 ± 137 versus 153 ± 74 mg/session), while urea removal was not different.
Conclusions. The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/Vurea during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity.
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TL;DR: A systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding, and the data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfates and support their roles in vascular and renal disease progression.
Abstract: A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.
501 citations
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TL;DR: Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.
Abstract: If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.
233 citations
Cites background from "Selectively increasing the clearanc..."
...Increase in dialysate flow (QD) and dialyzer surface (KoA) is another way to increase the clearance of pCS [173]....
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TL;DR: Toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means and no trials have yet tested cardiovascular or mortality benefit.
Abstract: Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.
167 citations
Cites background from "Selectively increasing the clearanc..."
...Another means to keep the level on the dialysate side low is to increase the dialysate flow and dialyzer membrane size [12,78]....
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TL;DR: The application of a hollow fiber mixed matrix membrane (MMM) for removal of end stage renal disease waste solutes has permeation properties in the ultrafiltration range and it is estimated that these membranes would suffice to remove the daily production of these protein bound solutes.
125 citations
Cites background from "Selectively increasing the clearanc..."
...showed in vivo that removal of protein bound solutes increased by raising the dialyzate flow rates [25]....
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TL;DR: Molecular 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.
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.
113 citations
References
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Baylor College of Medicine1, Cleveland Clinic2, University of Utah3, University of Illinois at Chicago4, National Institutes of Health5, University of Alabama6, Emory University7, Washington University in St. Louis8, University of California, Davis9, Tufts University10, Yeshiva University11, Harvard University12, University of Rochester13, Wake Forest University14, Vanderbilt University15, Duke University16
TL;DR: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.
Abstract: Background The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain. Methods We undertook a randomized clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. Results In the standard-dose group, the mean (±SD) urea-reduction ratio was 66.3±2.5 percent, the single-pool Kt/V was 1.32±0.09, and the equilibrated Kt/V was 1.16±0.08; in the high-dose group, the values were 75.2±2.5 percent, 1.71±0.11, and 1.53±0.09, respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was 3±7 ml per minute in the low-flux group and 34±11 ml per minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as com...
1,670 citations
TL;DR: Concentrations of retention solutes in uremia vary over a broad range, from nanograms per liter to grams per liter, and a substantial number of molecules are protein bound and/or middle molecules, and many of these exert toxicity and are characterized by a high range of toxic over normal concentration (CU/CN ratio).
1,404 citations
TL;DR: The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.
Abstract: Background and objectives: As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients.
Design, setting, participants, & measurements: One-hundred and thirty-nine patients (mean ± SD age: 67 ± 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled.
Results: Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 ± 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification.
Conclusions: The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.
740 citations
TL;DR: This preliminary study revealed that frequent nocturnal hemodialysis improved left ventricular mass, reduced the need for blood pressure medications, improved some measures of mineral metabolism, and improved selected measures of quality of life.
Abstract: ContextMorbidity and mortality rates in hemodialysis patients remain excessive. Alterations in the delivery of dialysis may lead to improved patient outcomes.ObjectiveTo compare the effects of frequent nocturnal hemodialysis vs conventional hemodialysis on change in left ventricular mass and health-related quality of life over 6 months.Design, Setting, and ParticipantsA 2-group, parallel, randomized controlled trial conducted at 2 Canadian university centers between August 2004 and December 2006. A total of 52 patients undergoing hemodialysis were recruited.InterventionParticipants were randomly assigned in a 1:1 ratio to receive nocturnal hemodialysis 6 times weekly or conventional hemodialysis 3 times weekly.Main Outcome MeasuresThe primary outcome was change in left ventricular mass, as measured by cardiovascular magnetic resonance imaging. The secondary outcomes were patient-reported quality of life, blood pressure, mineral metabolism, and use of medications.ResultsFrequent nocturnal hemodialysis significantly improved the primary outcome (mean left ventricular mass difference between groups, 15.3 g, 95% confidence interval [CI], 1.0 to 29.6 g; P = .04). Frequent nocturnal hemodialysis did not significantly improve quality of life (difference of change in EuroQol 5-D index from baseline, 0.05; 95% CI, −0.07 to 0.17; P = .43). However, frequent nocturnal hemodialysis was associated with clinically and statistically significant improvements in selected kidney-specific domains of quality of life (P = .01 for effects of kidney disease and P = .02 for burden of kidney disease). Frequent nocturnal hemodialysis was also associated with improvements in systolic blood pressure (P = .01 after adjustment) and mineral metabolism, including a reduction in or discontinuation of antihypertensive medications (16/26 patients in the nocturnal hemodialysis group vs 3/25 patients in the conventional hemodialysis group; P < .001) and oral phosphate binders (19/26 patients in the nocturnal hemodialysis group vs 3/25 patients in the conventional dialysis group; P < .001). No benefit in anemia management was seen with nocturnal hemodialysis.ConclusionThis preliminary study revealed that, compared with conventional hemodialysis (3 times weekly), frequent nocturnal hemodialysis improved left ventricular mass, reduced the need for blood pressure medications, improved some measures of mineral metabolism, and improved selected measures of quality of life.Trial Registrationisrctn.org Identifier: ISRCTN25858715
670 citations
Wake Forest University1, University of Virginia2, Cleveland Clinic3, University of Utah4, University Health Network5, Stanford University6, University of California, San Francisco7, University of British Columbia8, University of Western Ontario9, Case Western Reserve University10, Humber River Regional Hospital11, Ohio State University12, University of Iowa13, University of Pittsburgh14, Yale University15
TL;DR: Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes.
446 citations