Background: Ergothioneine is a diet-derived antioxidant with a specific membrane transporter that uptakes it into tissues susceptible to oxidative stress. We previously found that efficient dialytic clearance leads to marked ergothioneine depletion in patients on hemodialysis. Continuous renal replacement therapy (CRRT) provides higher time-averaged clearances of small solutes than hemodialysis. We therefore examined whether ergothioneine is depleted in patients receiving CRRT. Methods: We first compared erythrocyte and plasma ergothioneine levels in 19 critically ill subjects maintained on CRRT for ≥2 days (CRRT), 18 critically ill subjects without kidney impairment (CI), and 15 healthy subjects (control). We then examined the degree to which initiation of CRRT reduced ergothioneine levels in a separate group of 11 subjects after ≥2 days on CRRT and measured ergothioneine in the effluent fluid to calculate its CRRT clearance. Results: Compared to controls, erythrocyte and plasma ergothioneine levels were depleted in both critically ill subjects maintained on CRRT for 20 ± 26 days and critically ill subjects not on CRRT (erythrocyte: CRRT 226 ± 121 μM, CI 208 ± 132 μM, control 593 ± 568 μM; plasma: CRRT 0.52 ± 0.37 μM, CI 0.86 ± 0.83 μM, control 2.3 ± 1.7 μM). Initiation of CRRT in a separate group of 11 subjects significantly reduced the plasma level but not the erythrocyte level of ergothioneine after 3.4 ± 1.0 days. CRRT provided similar efficient clearances of ergothioneine, urea, and creatinine (31 ± 8, 38 ± 8, and 36 ± 10 mL/min). Conclusions: Ergothioneine is significantly depleted in critically illness, and prolonged CRRT may worsen the depletion. Our findings motivate further investigation of the impact of ergothioneine depletion in critical illness.

INTRODUCTION:Uric acid levels are commonly elevated in patients maintained on hemodialysis because hemodialysis provides a lower time-average uric acid clearance than the native kidney. However continuous kidney replacement therapy (CKRT) provides higher time-averaged clearances of small solutes than hemodialysis. We therefore examined whether the high small solute clearance provided by CKRT would reduce plasma uric acid levels below normal. METHODS:We measured plasma levels of uric acid and other selected solutes in 10 patients initiating CKRT and in 17 patients maintained on CKRT for 5 - 110 days. We estimated solute generation rates from their removal rates. The removal rates of uric acid and phosphate were estimated from their plasma levels while those of urea and creatinine were calculated directly from their effluent levels. CKRT prescription met current guidelines (24 ± 2 ml/kg/hr in patients initiating CKRT and 26 ± 3 ml/kg/hr in patients maintained longer on CKRT). RESULTS:Plasma uric acid levels declined from 8.7 ± 3.0 mg/dL to 1.8 ± 0.5 mg/dL after 2 to 4 days of initiating CKRT (p < 0.001) and were similarly low at 1.7 ± 0.6 mg/dL during ongoing CKRT. Plasma uric acid levels at both intervals were below the normal range. The average uric acid removal rate was not different at 2-4 days post-initiation (922 ± 367 mg/day) and during ongoing CKRT (855 ± 346 mg/day). CONCLUSION:CKRT prescribed according to current guidelines reduces uric acid levels below normal. The clinical consequences of low uric acid levels in this setting are unknown.

BackgroundAt low levels of kidney function, uremic symptoms prompt the initiation of dialysis. Peritoneal dialysis can continue to relieve these symptoms even when patients become anuric. To accomplish this, dialysis must maintain the plasma levels of solutes which cause symptoms lower than they were when dialysis was initiated. This study examined kinetic properties that solutes must possess for peritoneal dialysis to accomplish this. We sought further to identify solutes that possess these properties.MethodsMathematical modeling analyzed kinetic properties that determine a solute's plasma level in an anuric dialysis patient relative to its level when symptoms prompt dialysis initiation. The predictions of modeling were compared to the observed behavior of the solutes methylurea, guanidine, and phenylacetylglutamine measured in 22 patients on peritoneal dialysis and 22 patients with advanced chronic kidney disease using liquid chromatography tandem mass spectrometry.ResultsModeling showed that peritoneal dialysis can effectively control the plasma levels only of solutes which have a high dialytic clearance relative to their native kidney clearance. Chemical measurements showed that the dialytic clearance of methylurea was close to that of urea while the dialytic clearances of guanidine and phenylacetylglutamine were lower. Comparison of these dialytic clearances with residual native kidney clearances suggested that if their generation rates remained stable, peritoneal dialysis could control the levels of methylurea but not guanidine or phenylacetylglutamine in anuric patients.ConclusionA search for solutes whose properties include a high dialytic clearance and a relatively low native kidney clearance could identify solutes that contribute to uremic symptoms.

Background: If the GFR falls far enough, uremic symptoms such as anorexia and nausea prompt the initiation of dialysis. Thrice weekly hemodialysis can prevent recurrence of these symptoms even when patients become anuric. To accomplish this it must maintain the plasma levels of the uremic solutes which cause these symptoms lower than they were when dialysis was initiated. This study examined kinetic properties that solutes must possess for hemodialysis to accomplish this. We also sought to identify uremic solutes that possess these properties. Methods: Mathematical modeling analyzed how a solute's kinetic properties would determine the relation of its level in an anuric dialysis patients to its level when uremic symptoms prompt dialysis initiation. The previously unstudied solute methylurea was assayed by liquid chromatography tandem mass spectrometry (LC/MS/MS) in 13 participants on hemodialysis, 9 participants with advanced CKD, and 10 participants without kidney disease. Results: Mathematical modeling showed that conventional dialysis can effectively control the plasma levels better than the failing native kidneys only of solutes which have a high dialytic clearance relative to their native kidney clearance and a large volume of distribution. LC/MS/MS measurements showed that methylurea has these properties. The dialytic clearance of methylurea was 255 ± 32 ml/min and its volume of distribution was 1.09 ± 0.25 times the body water volume in hemodialysis patients. The methylurea clearance was lower than the GFR in patients without kidney disease (fractional clearance 0.44 ± 0.19) and patients with advanced CKD (fractional clearance 0.53 ± 0.10). Literature review revealed that urea was the only solute previously known to possess these properties. Conclusions: A further search for solutes whose properties include a high dialytic clearance, a relatively low native kidney clearance, and a high volume of distribution could help identify solutes that contribute to uremic symptoms.

Solutes that accumulate when the kidneys fail range in size from approximately 40 to 40,000 Da. Their dialytic clearance tends to decrease as their size increases. Disproportionate accumulation of large solutes has therefore long been considered a potential contributor to residual illness in patients on dialysis. Early efforts focused on the removal of middle molecules with mass from 300 to 2000 Da. The identification of amyloidosis caused by ß2 microglobulin ( ß2 M) with mass 12,000 Da shifted the focus to low-molecular weight proteins. High-flux dialysis and hemodiafiltration increase the clearance of these larger solutes. However, nonkidney clearance and solute compartmentalization limit the extent to which their plasma levels can be lowered by increasing their clearance during treatments of standard duration. Clinical benefits of high-volume hemodiafiltration thus cannot readily be accounted for by a reduction in the levels of known large solutes. The accumulation of peptides in the original middle molecular range and the clearance of larger solutes by peritoneal dialysis have been largely neglected. There is new interest in increasing the clearance of solutes even larger than ß2 M by extended dialysis. Ongoing clinical trials will extend our knowledge of the effects of extended dialysis and hemodiafiltration. In the future, we might more effectively reduce plasma large-solute levels by manipulating their nonkidney clearance, which is now poorly understood. ß2 M is the only large solute whose accumulation in kidney failure has been shown to have specific ill effects. Identification of the ill effects of other large solutes might prompt the development of more targeted therapies.

BACKGROUND:The 2015 Update of the Kidney Disease Outcomes Quality Initiative (KDOQI) Guideline for Hemodialysis Adequacy increased the contribution of residual kidney function in calculating standard Kt/V urea (stdKt/V urea ). However, no study has assessed the effect of prescribing twice weekly hemodialysis according to this guideline on patients' quality of life or uremic solute levels.METHODS:Twenty six hemodialysis patients with average residual urea clearance (Kru) 4.7±1.8 ml/min and hemodialysis vintage of 12±15 months (range two months to 4.9 years) underwent a cross-over trial comparing four weeks of twice weekly hemodialysis and four weeks of thrice weekly hemodialysis. Twice weekly hemodialysis was prescribed to achieve stdKt/V urea 2.2 incorporating Kru using the 2015 KDOQI Guideline. Thrice weekly hemodialysis was prescribed to achieve spKt/V urea 1.3 regardless of Kru. Quality of life and plasma levels of secreted uremic solutes and β 2 microglobulin (β 2 m) were assessed at the end of each period.RESULTS:Equivalence testing between twice and thrice weekly hemodialysis based on the Kidney Disease Quality of Life instrument (primary analysis) was inconclusive. Symptoms as assessed by the secondary outcomes Dialysis Symptom Index and post-dialysis recovery time were not worse with twice weekly hemodialysis. StdKt/V urea was adequate during twice weekly HD (2.7±0.5), and ultrafiltration rate and plasma potassium were controlled with minimally longer treatment times (twice weekly: 195±20 vs. thrice weekly: 191±17 minutes). Plasma levels of the secreted solutes and β 2 m were not higher with twice weekly than thrice weekly hemodialysis.CONCLUSIONS:Twice weekly hemodialysis can be prescribed using the higher contribution assigned to Kru by the 2015 KDOQI Guideline. With twice weekly hemodialysis, quality of life was unchanged, and the continuous function of the residual kidneys controlled fluid gain and plasma levels of potassium and uremic solutes without substantially longer treatment times.

IntroductionUremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis.MethodsWe measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models.ResultsThe mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma.ConclusionQuinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.

In this issue, Randall et al.1 address whether experimental renal insufficiency reproducibly changes the colon microbiome. They report a meta-analysis of stool/colon microbiome data from studies of mice or rats. Data from ten studies reveal no common microbiome profile associated with renal insufficiency, and comparison of specific findings across studies shows only some weak qualitative similarities. Overall, their results weaken the hypothesis that a reproducibly defined set of microbiome alterations, or "uremic dysbiosis," is a cause or consequence of renal insufficiency. Control animals in different studies are shown to have had widely different microbiomes, suggesting a basis for the variable findings among studies. The findings of Randall et al. should be placed in the context of our rapidly expanding knowledge of the colon microbiota and its chemical products. The 1970s marked the beginning of genetic classification of bacteria on the basis of the sequence of the gene for the small subunit of ribosomal RNA (known as 16S rRNA).2 This gene's highly conserved regions identify it as bacterial, while its interspersed variable regions act as a "molecular clock" and reveal the degree to which different microbes are genetically related. The application of PCR and automated DNA sequencing has revealed the existence of many thousands of new colon microbes, most of which cannot readily be grown in culture. The microbial composition of diverse types of samples (e.g., of stool, sea water, and soil) is therefore now most often established by relating the 16S rRNA gene sequences in DNA extracted from the samples to large databases of 16S rRNA gene sequences. Microbial species, or amplicon sequencing variants, are defined by their 16S rRNA sequences, while broader taxonomic groupings such as the phyla discussed by Randall et al. include microbes whose 16S rRNA sequences have a defined degree of similarity and are therefore more closely related to one another evolutionarily. Importantly, the functional properties of microbes cannot be perfectly inferred from their 16S rRNA sequences. Microbes with identical 16S rRNA gene sequences may have different metabolic capacities due to genetic changes that are independent of the 16S rRNA gene, such as acquiring a metabolic capacity through horizontal gene transfer. Improved computational methods and reduced sequencing costs have spurred 16S rRNA analysis of the colon and other microbiomes in health and in disease. This work, as exemplified by the National Institutes of Health Human Microbiome Project launched in 2007, has opened a world of surprises.3 The 200 gram cell mass of the colon microbiome is seen to include hundreds of bacterial species in individual humans. The colon microbiome is somewhat limited in diversity, including only two to ten common phyla of the >100 microbial phyla identified to date. However the proportion of these phyla varies widely among healthy humans (Figure 1). Further studies have shown that the mix of colon microbes in individual adult humans remains relatively stable over years and tends to return toward its original composition after major perturbations such as those occasioned by antibiotic use. The health impact of the wide disparity among colon microbiomes in healthy humans in industrialized countries remains to be established. The causes of this disparity are also largely uncertain. Hypothesized influences include differences in the human host's gut motility and genetic makeup along with early exposure to different microbes. Diet is also an obvious potential influence. Of note, however, the variability among the colon microbiomes of healthy Americans was not reduced by exposure to a uniform modern American diet over 7 days.4 Exposure to different diets and for longer periods may produce greater changes, as observed with increased microbiome diversity when participants consumed high levels of fermented foods for 6 weeks.5Figure 1: Microbiomes that vary in composition are often functionally similar. The composition of 242 stool samples from healthy US adults (top) as assessed by 16S rRNA amplicon sequencing varies substantially more between individuals than functional capacity (bottom) as assessed by metagenomic sequencing. Each vertical bar represents one individual, and colors represent phyla (top) and broad functional categories predicted for gene sequences (bottom). The figure shows stool data abstracted from Figure 2 of the 2012 report of the Human Microbiome Project.3Wide differences among healthy subjects have made it difficult to define a "healthy" microbiome. Extensive efforts to identify changes in the microbiome characteristic of disease states other than renal insufficiency have also had limited success. Perhaps not surprisingly, the most dramatic changes have been associated with active inflammatory bowel disease.6 Here is important to distinguish between the microbiome's composition as defined by the proportion of different phylogenetic groups and the microbiome's metabolic function(s). Continued developments in sequencing and computational methods now allow the genomes of different microbial species to be reconstructed from samples of mixed microbial DNA. This "metagenomic" analysis allows characterization of the microbiome according to the prevalence of all genes within the sample, including those involved in metabolic processes. A remarkable finding of the Human Microbiome Project was that microbiomes of widely differing phylogenetic composition (determined by 16S rRNA sequencing, Figure 1, top) encoded similar metabolic functions (determined by metagenomics, Figure 1 bottom). With the functional capacity of different microbes in mind, we should consider what might cause colon microbial alterations in CKD. Metagenomic analysis might confirm the suggestion that high urea and uric acid concentrations promote the growth of colon microbes possessing urease and uricase.7 However, even an analysis of the microbiome's genetic capacity does not provide a reliable measure of its metabolic activity. Assessment of colon microbial activity on the basis of analysis of mRNAs (metatranscriptomics), proteins (metaproteomics), or metabolites (metabolomics) has not been as widely used for reasons including the cost and technological challenges of these approaches. Indeed, 16S sequencing and metagenomics only partially avoid these challenges because variable recovery of microbial DNA from stool samples likely introduces error in the description of the microbiome's genetic profile. The experimental data analyzed by Randall et al. were obtained largely in animals with about one-third normal renal function. As they describe, human studies have also so far not identified a reproducible change in the microbiome characteristic of more advanced renal failure. As they note, references to "uremic dysbiosis" thus seem premature. The colon microbiome may however contribute to the ill effects of renal failure without any change in its composition. It produces numerous compounds foreign to mammalian metabolism which, often after conjugation by the liver, are normally excreted by the kidneys.8 Well-known examples are the amino acid breakdown products indoxyl sulfate and p-cresol sulfate. As cited by Randall et al., human studies suggest that end-stage renal failure does not greatly affect the production of the best known of these compounds and that differences in microbial metabolite production in humans with and without renal function are due more to differences in diet than to renal failure.9,10 The accumulation of such compounds has been considered to promote illness in two ways. First, their accumulation could cause "uremic" symptoms in patients with advanced CKD. Second, their accumulation could accelerate the progression of CKD. Other studies have suggested that increased entry into the circulation of endotoxin and other large microbially derived substances causes inflammation in advanced CKD. Ultimately, we can prove that the colon microbiome causes illness only if we can modify illness by manipulating it. Such proof, which may be considered to represent fulfillment of a modified version of Koch postulates, has not been obtained in human renal disease. Human health benefit has been obtained from fecal transplantation for recurrent C. difficile infection. In renal disease, feeding dietary fiber has been found to reduce the production of selected colon-derived solutes in patients and to limit the progression of CKD in animals. Overall, the microbiome has proven hard to manipulate. Selected microbes introduced as probiotics in animals and humans with established microbiomes generally do not persist. Efforts are now directed toward the development of "designer microbiomes" with specific metabolic capacities which could eventually be installed in diseased humans to reprogram metabolic output and alter aspects of host biology in beneficial ways.11 More detailed knowledge of the microbiome and its products will hopefully direct future testing of whether such manipulation of the microbiome can alleviate illness in patients with renal failure. Disclosures Dr. Fischbach is a co-founder and director of Federation Bio and Viralogic, a co-founder of Revolution Medicines, a member of the scientific advisory. M. Fischbach also reports Consultancy: NGM Bio; Ownership Interest: Kelonia, NGM Bio; Patents or Royalties: Federation Bio; and Advisory or Leadership Role: Federation Bio, Kelonia, Board of NGM Biopharmaceuticals, and an innovation partner at The Column Group. Dr. Sonnenberg is a co-founder of Novome Biotechnologies, January AI, and Interface Biosciences; he serves on the scientific advisory board of BCD Biosciences. J. Sonnenburg also reports Ownership Interest: BCD Biosciences, Second Genome; Research Funding: Abbott Nutrition, Clorox; Honoraria: Biocodex Microbiota Foundation (spouse, SAB), The Cranberry Institute (spouse, SAB); and Patents or Royalties: Novome Biotechnologies. Dr. Meyer has served as a consultant for Baxter. T. Meyer also reports Research Funding: Outset Medical; Honoraria: Renal Research Institute; and Advisory or Leadership Role: ASN editorial board, KI editorial board. The remaining author has nothing to disclose. Funding This work was supported by a National Institutes of Health award (R01 DK118426). Dr. Guthrie received further support from a Howard Hughes Medical Institute Hanna H. Gray fellowship. Author Contributions M.A. Fischbach, L. Guthrie, T. Meyer, and J.L. Sonnenburg conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.

Key Points Conventional hemodialysis provides limited clearance of uremic solutes that bind to plasma proteins. No studies have yet tested whether increasing the clearance of bound solutes provides clinical benefit. Practical means to increase the dialytic clearance of bound solutes are required to perform such studies. Background Conventional hemodialysis provides limited clearance of uremic solutes that bind to plasma proteins. However, no studies have tested whether increasing the clearance of bound solutes provides clinical benefit. Practical means to increase the dialytic clearance of bound solutes are required to perform such studies. Methods Artificial plasma was dialyzed using two dialysis systems in series. In the first recirculating system, a fixed small volume of dialysate flowed rapidly through an activated carbon block before passing through two large dialyzers. In a second conventional system, a lower flow of fresh dialysate was passed through a single dialyzer. Chemical measurements tested the ability of the recirculating system to increase the clearance of selected solutes. Mathematical modeling predicted the dependence of solute clearances on the extent to which solutes were taken up by the carbon block and were bound to plasma proteins. Results By itself, the conventional system provided clearances of the tightly bound solutes p-cresol sulfate and indoxyl sulfate of only 18±10 and 19±11 ml/min, respectively (mean±SD). Because these solutes were effectively adsorbed by the carbon block, the recirculating system by itself provided p-cresol sulfate and indoxyl sulfate clearances of 45±11 and 53±16 ml/min. It further raised their clearances to 54±12 and 61±17 ml/min when operating in series with the conventional system ( P < 0.002 versus conventional clearance both solutes). Modeling predicted that the recirculating system would increase the clearances of bound solute even if their uptake by the carbon block was incomplete. Conclusions When added to a conventional dialysis system, a recirculating system using a carbon block sorbent, a single pump, and standard dialyzers can greatly increase the clearance of protein-bound uremic solutes.

ABSTRACT:Peritoneal dialysis (PD) is now commonly prescribed to achieve target clearances for urea or creatinine. The International Society for Peritoneal Dialysis has proposed however that such targets should no longer be imposed. The Society's new guidelines suggest rather that the PD prescription should be adjusted to achieve well-being in individual patients. The relaxation of treatment targets could allow increased use of PD. Measurement of solute levels in patients receiving dialysis individualized to relieve uremic symptoms could also help us identify the solutes responsible for those symptoms and then devise new means to limit their accumulation. This possibility has prompted us to review the extent to which different uremic solutes are removed by PD.

The adequacy of hemodialysis is now assessed by measuring the removal of the single-solute urea. The urea clearance provided by contemporary dialysis is a large fraction of the blood flow through the dialyzer and therefore cannot be increased much further. Other solutes however likely contribute more than urea to the residual uremic illness suffered by hemodialysis patients. We here review methods which could be employed to increase the clearance of nonurea solutes. We will separately consider the clearances of free low-molecular-mass solutes, free larger solutes, and protein-bound solutes. New clinical studies will be required to test the extent to which increasing the clearance on nonurea solutes with these various characteristics can improve patients' health.

BACKGROUND AND OBJECTIVES:Adsorption of uremic solutes to activated carbon provides a potential means to limit dialysate volumes required for new dialysis systems. The ability of activated carbon to take up uremic solutes has, however, not been adequately assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Graded volumes of waste dialysate collected from clinical hemodialysis treatments were passed through activated carbon blocks. Metabolomic analysis assessed the adsorption by activated carbon of a wide range of uremic solutes. Additional experiments tested the ability of the activated carbon to increase the clearance of selected solutes at low dialysate flow rates. RESULTS:Activated carbon initially adsorbed the majority, but not all, of 264 uremic solutes examined. Solute adsorption fell, however, as increasing volumes of dialysate were processed. Moreover, activated carbon added some uremic solutes to the dialysate, including methylguanidine. Activated carbon was particularly effective in adsorbing uremic solutes that bind to plasma proteins. In vitro dialysis experiments showed that introduction of activated carbon into the dialysate stream increased the clearance of the protein-bound solutes indoxyl sulfate and p-cresol sulfate by 77%±12% (mean±SD) and 73%±12%, respectively, at a dialysate flow rate of 200 ml/min, but had a much lesser effect on the clearance of the unbound solute phenylacetylglutamine. CONCLUSIONS:Activated carbon adsorbs many but not all uremic solutes. Introduction of activated carbon into the dialysate stream increased the clearance of those solutes that it does adsorb.

Gut microbiota metabolism of dietary compounds generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS), and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDM generation; however, it is unclear if inter-individual differences in diet or gut microbiome dominantly contribute to MDM variance. Here, we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. During dietary homogeneity, the coefficient of variation in PAG, PCS, and IS (primary outcome) did not decrease, nor did inter-individual variation in most identified metabolites; other microbiome metrics showed no or modest responses to the intervention. Host identity and age are dominant contributors to variability in MDMs. These results highlight the potential need to pair dietary modification with microbial therapies to control MDM profiles.

BACKGROUND AND OBJECTIVES:Residual native kidney function confers health benefits in patients on dialysis. It can facilitate control of extracellular volume and inorganic ion concentrations. Residual kidney function can also limit the accumulation of uremic solutes. This study assessed whether lower plasma concentrations of uremic solutes were associated with residual kidney function in pediatric patients on peritoneal dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Samples were analyzed from 29 pediatric patients on peritoneal dialysis, including 13 without residual kidney function and ten with residual kidney function. Metabolomic analysis by untargeted mass spectrometry compared plasma solute levels in patients with and without residual kidney function. Dialytic and residual clearances of selected solutes were also measured by assays using chemical standards. RESULTS:Metabolomic analysis showed that plasma levels of 256 uremic solutes in patients with residual kidney function averaged 64% (interquartile range, 51%-81%) of the values in patients without residual kidney function who had similar total Kt/Vurea. The plasma levels were significantly lower for 59 of the 256 solutes in the patients with residual kidney function and significantly higher for none. Assays using chemical standards showed that residual kidney function provides a higher portion of the total clearance for nonurea solutes than it does for urea. CONCLUSIONS:Concentrations of many uremic solutes are lower in patients on peritoneal dialysis with residual kidney function than in those without residual kidney function receiving similar treatment as assessed by Kt/Vurea.

Significance Statement In patients with CKD, the clearance of waste solutes removed by tubular secretion may be altered to an extent that is disproportionate to the reduction in the GFR. However, an average change in the clearance of secreted waste solutes relative to the GFR in CKD has not been reported, possibly because studies performed so far have included few subjects with advanced CKD. The authors found that the secretory clearance of many waste solutes is reduced relative to the GFR in patients with an eGFR<12 ml/min per 1.73 m2. As patients approach dialysis, to the extent that secreted solutes contribute to uremic symptoms, reductions in fractional clearances of secreted solutes might cause such symptoms to increase out of proportion to the reduction in GFR. Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the GFR in CKD. Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. Methods To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 patients with CKD and an eGFR of 7±2 ml/min per 1.73 m2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in patients with CKD and to those of creatinine in controls. Results Metabolomic analysis identified 39 secreted solutes with fractional clearance >3.0 in control participants. Fractional clearance values in patients with CKD were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p-cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for patients with CKD; P<0.001), p-cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for patients with CKD; P<0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8; P<0.001) but not for hippurate (10.2±3.8 versus 8.4±2.6; P=0.13). Conclusions Secretory clearances for many solutes are reduced more than the GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.