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Background: Impairment of kidney function is routinely assessed by measuring the accumulation of creatinine, an organic solute cleared largely by glomerular filtration. We tested whether the clearance of solutes that undergo tubular secretion is reduced in proportion to the clearance of creatinine in humans with AKI., Methods: Four endogenously produced organic solutes (phenylacetylglutamine [PAG], hippurate [HIPP], indoxyl sulfate [IS], and p-cresol sulfate [PCS]) were measured in spot urine and plasma samples from ten patients with AKI and 17 controls. Fractional clearance relative to creatinine was calculated to assess tubular secretion. Fractional clearance values were calculated in terms of the free, unbound levels of HIPP, IS, and PCS that bind to plasma proteins., Results: Fractional clearance values for PAG, HIPP, IS, and PCS were >1.0 in patients with AKI as well as controls, indicating that these solutes were still secreted by the tubules of the injured kidneys. Fractional clearance values were, however, significantly lower in patients with AKI than controls, indicating that kidney injury reduced tubular secretion more than glomerular filtration (AKI versus control: PAG, 2.1±0.7 versus 4.6±1.4, P <0.001; HIPP, 10±5 versus 15±7, P =0.02; IS, 10±6 versus 28±7, P <0.001; PCS, 3.3±1.8 versus 10±3, P <0.001). Free plasma levels rose out of proportion to total plasma levels for each of the bound solutes in AKI, so that calculating their fractional clearance in terms of their total plasma levels failed to reveal their impaired secretion., Conclusions: Tubular secretion of organic solutes can be reduced out of proportion to glomerular filtration in AKI. Impaired secretion of protein-bound solutes may be more reliably detected when clearances are expressed in terms of their free, unbound levels in the plasma.

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants., (Published by Elsevier Inc.)

The uremic syndrome is attributed to progressive retention of compounds that, under normal conditions, are excreted by the healthy kidneys. p-cresol sulfate (PCS), a prototype protein-bound uremic retention solute, has been shown to exert toxic effects in vitro. Recent studies have identified relations between increased levels of PCS and indoxyl sulfate (IS) and adverse clinical outcomes in hemodialysis patients. We explored the relationship between free and total PCS and IS with infection-related hospitalizations (IH) and septicemia in 2 cohorts, Choices for Healthy Outcomes in Caring for end-stage renal disease (ESRD) Study (CHOICE) and Hemodialysis Study (HEMO).We measured free and total levels of PCS and IS in stored specimens in CHOICE, a cohort of 464 incident hemodialysis patients enrolled in 1995 to 1998 and followed for an average of 3.4 years and in a prevalent dialysis cohort of 495 patients enrolled in HEMO from 1995 to 2000 and followed for an average of 4.4 years. We measured free PCS and IS using mass spectroscopy. The 2 cohorts were linked to United States Renal Data System (USRDS) Medicare billing records to ascertain IH over follow-up. We examined the association of free and total levels of PCS and IS with IH and septicemia using multilevel Poisson regression models adjusted for demographics, comorbidities, clinical factors, and laboratory tests including residual kidney function. We stratified patients a priori based on gastrointestinal (GI) disease as PCS and IS are produced in colon.In CHOICE, highest tertile of free PCS in multivariable model was associated with 50% higher risk of IH [95% CI = 1.01-2.23] compared with lowest tertile in patients with no-GI disease. A significant trend was noted between greater levels of free PCS and septicemia in no-GI disease group in both cohorts, while no association was noted in GI disease group. Total PCS concentrations were not associated with either IH or septicemia in either cohort. No significant risk of IH or septicemia was noted with higher levels of free or total IS in either GI or no-GI disease group.These results suggest an association between higher concentrations of free PCS and infection-related and sepsis-related hospitalizations in hemodialysis patients. Better methods of dialysis should be developed to evaluate the utility of removing PCS and its effect on the outcome and also therapies to decrease gastrointestinal tract production of uremic solutes.

Background: The protein-bound solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) accumulate to high plasma levels in renal failure and have been associated with adverse events. The clearance of these bound solutes can be altered independently of the urea clearance by changing the dialysate flow and dialyzer size. This study tested whether a sustained difference in clearance would change the plasma levels of PCS and IS., Methods: Fourteen patients on thrice-weekly nocturnal hemodialysis completed a crossover study of two periods designed to achieve widely different bound solute clearances. We compared the changes in pre-dialysis plasma PCS and IS levels from baseline over the course of the two periods., Results: The high-clearance period provided much higher PCS and IS clearances than the low-clearance period (PCS: 23 ± 4 mL/min versus 12 ± 3 mL/min, P < 0.001; IS: 30 ± 5 mL/min versus 17 ± 4 mL/min, P < 0.001). Despite the large difference in clearance, the high-clearance period did not have a different effect on PCS levels than the low-clearance period [from baseline, high: +11% (-5, +37) versus low: -8% (-18, +32), (median, 25th, 75th percentile), P = 0.50]. In contrast, the high-clearance period significantly lowered IS levels compared with the low-clearance period [from baseline, high: -4% (-17, +1) versus low: +22% (+14, +31), P < 0.001). The amount of PCS removed in the dialysate was significantly greater at the end of the high-clearance period [269 (206, 312) versus 199 (111, 232) mg per treatment, P < 0.001], while the amount of IS removed was not different [140 (87, 196) versus 116 (89, 170) mg per treatment, P = 0.15]., Conclusions: These findings suggest that an increase in PCS generation prevents plasma levels from falling when the dialytic clearance is increased. Suppression of solute generation may be required to reduce plasma PCS levels in dialysis patients., (Published by Oxford University Press on behalf of ERA-EDTA 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background and Objectives: Numerous uremic solutes are derived from the action of colon microbes. Two such solutes, indoxyl sulfate and p-cresol sulfate, have been associated with adverse outcomes in renal failure. This study tested whether increasing dietary fiber in the form of resistant starch would lower the plasma levels of these solutes in patients on hemodialysis., Design, Setting, Participants, & Measurements: Fifty-six patients on maintenance hemodialysis were randomly assigned to receive supplements containing resistant starch (n=28) or control starch (n=28) daily for 6 weeks in a study conducted between October 2010 and May 2013. Of these, 40 patients (20 in each group) completed the study and were included in the final analysis. Plasma indoxyl sulfate and p-cresol sulfate levels were measured at baseline and week 6., Results: Increasing dietary fiber for 6 weeks significantly reduced the unbound, free plasma level of indoxyl sulfate (median -29% [25th percentile, 75th percentile, -56, -12] for fiber versus -0.4% [-20, 34] for control, P=0.02). The reduction in free plasma levels of indoxyl sulfate was accompanied by a reduction in free plasma levels of p-cresol sulfate (r=0.81, P<0.001). However, the reduction of p-cresol sulfate levels was of lesser magnitude and did not achieve significance (median -28% [-46, 5] for fiber versus 4% [-28, 36] for control, P=0.05)., Conclusions: Increasing dietary fiber in hemodialysis patients may reduce the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate without the need to intensify dialysis treatments. Further studies are required to determine whether such reduction provides clinical benefits., (Copyright © 2014 by the American Society of Nephrology.)

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.

Many small solutes excreted by the kidney are bound to plasma proteins, chiefly albumin, in the circulation. The combination of protein binding and tubular secretion allows the kidney to reduce the free, unbound concentrations of such solutes to lower levels than could be obtained by tubular secretion alone. Protein-bound solutes accumulate in the plasma when the kidneys fail, and the free, unbound levels of these solutes increase more than their total plasma levels owing to competition for binding sites on plasma proteins. Given the efficiency by which the kidney can clear protein-bound solutes, it is tempting to speculate that some compounds in this class are important uremic toxins. Studies to date have focused largely on two specific protein-bound solutes: indoxyl sulfate and p-cresyl sulfate. The largest body of evidence suggests that both of these compounds contribute to cardiovascular disease, and that indoxyl sulfate contributes to the progression of chronic kidney disease. Other protein-bound solutes have been investigated to a much lesser extent, and could in the future prove to be even more important uremic toxins., (Published by Elsevier Inc.)

The kidney clears numerous solutes from the plasma; however, retention of these solutes causes uremic illness when the kidneys fail. We know remarkably little about which retained solutes are toxic and this limits our ability to improve dialysis therapies. To explore this, we employed untargeted mass spectrometry to identify solutes that are efficiently cleared by the kidney. High-resolution mass spectrometry detected 1808 features in the urine and plasma ultrafiltrate of 5 individuals with normal renal function. The estimated clearance rates of 1082 peaks were greater than the creatinine clearance indicating tubular secretion. Further analysis identified 90 features representing solutes with estimated clearance rates greater than the renal plasma flow. Quantitative mass spectrometry with stable isotope dilution confirmed that efficient clearance of these solutes is made possible by the combination of binding to plasma proteins and tubular secretion. Tandem mass spectrometry established the chemical identity of 13 solutes including hippuric acid, indoxyl sulfate, and p-cresol sulfate. These 13 efficiently cleared solutes were found to accumulate in the plasma of hemodialysis patients, with free levels rising to more than 20-fold normal for all but two of them. Thus, further analysis of solutes efficiently cleared by secretion in the native kidney may provide a potential route to the identification of uremic toxins.

Background: Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality., Methods: We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index., Results: Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043)., Conclusions: In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.

Background and Objectives: The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores., Design, Setting, Participants, & Measurements: The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart., Results: Average PCS excretion was 62% lower (95% confidence interval [95% CI], 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month., Conclusions: PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet.

Background: The uremic retention solutes indoxyl sulfate and p-cresyl sulfate are linked to cardiovascular disease and overall survival. Dialytic clearances are limited, which is principally attributed to tight protein binding. Extending dialysis duration would be expected to substantially increase protein-bound uremic solute removal. The aim of the current study was to study protein-bound uremic retention solute clearances and kinetics during longer-hours nocturnal hemodialysis., Methods: In a prospective cohort study of 32 maintenance alternate-night nocturnal hemodialysis patients, we followed serum concentrations, solute removals and solute clearances of p-cresyl sulfate and indoxyl sulfate. Spent dialysate sampling was fractionated to compare solute removals between the first 4 h and next 4 h of nocturnal dialysis. Single-compartment variable volume kinetics were calculated., Results: Dialytic clearances of protein-bound uremic retention solutes are maintained during nocturnal (longer-hours) dialysis. Clearances of indoxyl sulfate exceed those of p-cresyl sulfate, presumably due to less tight protein-binding. Apparent distribution volumes increase substantially during nocturnal dialysis, indicative of multi-compartmental behavior of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate., Conclusions: During nocturnal hemodialysis, serum concentrations of protein-bound solute concentrations are reduced less than predicted. Reduction ratios are not a valid tool to estimate total solute removal of protein-bound uremic retention solutes., (Copyright © 2011 S. Karger AG, Basel.)

Indoxyl sulfate and p-cresyl sulfate are protein-bound marker molecules in chronic kidney disease. Recent findings suggest that indoxyl sulfate and p-cresyl sulfate directly contribute to the uremic syndrome. A method for quantification of p-cresyl sulfate and indoxyl sulfate total serum concentrations was developed. We used sodium octanoate as competitor to replace non-covalent binding of p-cresyl sulfate and indoxyl sulfate to albumin. Total, within-run, between-run and between-day imprecision for indoxyl sulfate and p-cresyl sulfate were all below 6%. The limit of quantification was 3.2microM for both analytes. Recovery, tested in hemodialysis patients, was 102% for indoxyl sulfate and 105% for p-cresyl sulfate. Deming regression demonstrated good agreement for indoxyl sulfate between this new method and an external HPLC method. Method comparison for p-cresyl sulfate of the new method with our in-house GC-MS method demonstrated good agreement, whereas method comparison with an external HPLC method revealed a small proportional bias. Sodium octanoate binding competition is a novel sample preparation that allows for direct quantification of indoxyl sulfate and p-cresyl sulfate.

Purpose of Review: Our concept of uremia has expanded to encompass the illness patients begin to suffer as glomerular filtration rate declines long before the onset of end-stage renal disease (ESRD) not explained by known derangements in volume status or metabolic parameters. New insights into the accumulation of uremic toxins and the loss of function of hormones and enzymes provide important information on the etiology of uremia., Recent Findings: New data are accumulating on the identity and toxicity of uremic toxins and the syndromes that encompass uremia. rho-Cresol sulfate and indoxyl sulfate are small, protein-bound molecules that are poorly cleared with dialysis. These molecules have been linked to cardiovascular disease and oxidative injury. Impaired immunity plays a central role in the morbidity of ESRD and may be both the result of uremic toxicity and a contributor to oxidative stress in ESRD. Uremic cachexia is an underrecognized uremic syndrome. New insights into disordered feeding circuits in ESRD may lead to novel therapies using hormone agonists., Summary: Mortality in ESRD remains unacceptably high. It is hoped that as knowledge emerges on the causes and consequences of uremia, we are embarking on an era not only of new insights but also new and effective treatments for patients with the ill effects of uremia.

Background and Objectives: Protein-bound solutes are poorly cleared by peritoneal dialysis. We examined the hypothesis that plasma concentrations of bound solutes would therefore rise as residual renal function is lost., Design, Setting, Participants, & Measurements: Clearances of urea indican and p-cresol sulfate were measured in peritoneal dialysis patients with and without residual function., Results: In patients with residual function, protein binding restricted the peritoneal indican and p-cresol sulfate clearances to 0.3 +/- 0.1 ml/min, as compared to the peritoneal urea clearance of 5.5 +/- 1.1 ml/min. The urinary indican and p-cresol sulfate clearances of 2.7 +/- 2.5 and 1.3 +/- 1.0 ml/min were closer to the urinary urea clearance of 3.9 +/- 2.2 ml/min, reflecting the superior ability of native kidney function to clear bound solutes. Urinary clearance thus provided the majority of the total indican and p-cresol sulfate clearances of 3.0 +/- 2.5 and 1.6 +/- 1.0 ml/min in patients with residual function but the minority of total urea clearance of 9.4 +/- 2.2 ml/min. Loss of residual function lowered the total clearances for indican and p-cresol sulfate to 0.5 +/- 0.2 and 0.4 +/- 0.2 ml/min, whereas the urea clearance fell only slightly. However there was only a modest increase in the plasma indican level and no increase in the plasma p-cresol sulfate level in patients with no residual function because reduction in the daily removal of these solutes accompanied the reduction in their total clearance rates., Conclusions: Reduction in the removal of indican and p-cresol sulfate kept plasma levels from rising markedly when residual function was lost.

This study assessed the capacity of a cartridge containing coated granular carbon to clear protein-bound solutes. Clearances for test solutes were measured while an albumin solution representing plasma was pumped from a 10 L reservoir through the cartridge at a rate of 200 mL/min for 5 h. Clearance values for phenol red, phenytoin, and indican were well below the limit imposed by the plasma flow and declined with time. The clearance of phenol red, which was the most tightly bound solute, fell from 38 ± 12 to 17 ± 2 mL/min. Additional studies revealed that the cartridge contained enough carbon to absorb all the protein-bound test solutes, but that the rate of their clearance was limited by the inability of granular carbon to take up solutes rapidly at a low concentration. The rate of solute uptake at low concentration was shown to be much greater when carbon was in powdered rather than granular form. A device in which approximately 50 g of powdered carbon was recirculated in the dialysate compartment of hollow fiber kidneys cleared phenol red and phenytoin more rapidly than the hemoperfusion cartridge containing 300 g of coated granular carbon. These results indicate that hemoperfusion over coated granular carbon provides limited clearance of protein-bound solutes. [ABSTRACT FROM AUTHOR]