Dataset Information

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

ABSTRACT: Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume post-hemodiafiltration and 7 short-daily dialysis with the NxStage-One system. Instant dialysate/blood determinations were also performed at different times, and Kt was calculated as the product of the D/P ratio by volume of delivered dialysate plus UF. There were significant differences in single session and weekly Kt (whole dialysate and instant calculations) between methodologies, most notably for creatinine, phosphorus and beta2-microglobulin. Urea Kt messured in balance studies was almost equal to that derived from the usual plasma kinetic model-based Daugirdas' equation (eKt/V) and independent V calculation, indicating full correspondence. Non-urea solute Kt as a fraction of urea Kt (i.e. fractional removal relative to urea) showed significant differences between technologies, indicating non-proportional removal of non-urea solutes and urea. Instant Kt was higher than that in full balances, accounting for concentration disequilibrium between arterial and systemic blood, but measured and calculated quantitative solute removal were equal, as were qualitative Kt comparisons between technologies. Thus, we show that urea metrics may not reliably express removal efficiency of non-urea solutes, as indicated by Kt. Kt can easily be measured without whole dialysate collection, allowing to expand the metrics of dialytic efficiency to almost any non-urea solute removed by dialysis.

SUBMITTER: Colussi G

PROVIDER: S-EPMC7259768 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

Colussi Giacomo G Brunati Chiara Carla Maria CCM Gervasi Francesca F Montoli Alberto A Vergani Denise D Curci Federica F Minetti Enrico E

PloS one 20200529 5

Dialysis urea removal metrics may not translate into proportional removal efficiency of non-urea solutes. We show that the Kt factor (plasma volume totally cleared of any solutes) differentiates removal efficiency of non-urea solutes in different technologies, and can easily be calculated by instant blood-dialysate collections. We performed mass balances of urea, creatinine, phosphorus and beta2-microglobulin by whole dialysate collection in 4 low-flux and 3 high-flux hemodialysis, 2 high-volume ...[more]

PMID: 32469929

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Project description:BACKGROUND:There is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS. METHODS:We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment ("isohydric dialysis"). Eight stable hemodialysis patients underwent "isohydric dialysis" for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout. RESULTS:We found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of "isohydric dialysis" (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound. The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid. CONCLUSION:These findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration ("isohydric dialysis:"), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.

Project description:UNLABELLED:The colonic microbial metabolism is a key contributor to uremic retention solutes accumulating in patients with CKD, relating to adverse outcomes and insulin resistance. Whether prebiotics can reduce intestinal generation of these microbial metabolites and improve insulin resistance in CKD patients not yet on dialysis remains unknown. We performed a randomized, placebo-controlled, double-blind, cross-over study in 40 patients with eGFR between 15 and 45 ml/min/1.73 m2. Patients were randomized to sequential treatment with prebiotic arabinoxylan oligosaccharides (AXOS) (10 g twice daily) and maltodextrin for 4 weeks, or vice versa, with a 4-week wash-out period between both intervention periods. Serum levels and 24h urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, trimethylamine N-oxide and phenylacetylglutamine were determined at each time point using liquid chromatography-tandem mass spectrometry. In addition, insulin resistance was estimated by the homeostatic model assessment (HOMA-IR). A total of 39 patients completed the study. We observed no significant effect of AXOS on serum p-cresyl sulfate (P 0.42), p-cresyl glucuronide (P 0.59), indoxyl sulfate (P 0.70) and phenylacetylglutamine (P 0.41) and a small, albeit significant decreasing effect on serum trimethylamine N-oxide (P 0.04). There were neither effect of AXOS on 24h urinary excretion of p-cresyl sulfate (P 0.31), p-cresyl glucuronide (P 0.23), indoxyl sulfate (P 0.87) and phenylacetylglutamine (P 0.43), nor on 24h urinary excretion of trimethylamine N-oxide (P 0.97). In addition, we observed no significant change in HOMA-IR (P 0.93). In conclusion, we could not demonstrate an influence of prebiotic AXOS on microbiota derived uremic retention solutes and insulin resistance in patients with CKD not yet on dialysis. Further study is necessary to elucidate whether prebiotic therapy with other characteristics, higher cumulative exposure or in different patient populations may be of benefit. TRIAL REGISTRATION:Clinicaltrials.gov NCT02141815.

Project description:p-Cresol sulfate (pCS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of impaired kidney function. While pharmacologic provision of pCS or IS can promote pro-thrombotic phenotypes, neither the microbial enzymes involved nor direct gut microbial production have been linked to CVD. Untargeted metabolomics was performed on a discovery cohort (n = 1,149) with relatively preserved kidney function, followed by stable isotope-dilution mass spectrometry quantification of pCS and IS in an independent validation cohort (n = 3,954). Genetic engineering of human commensals to produce p-cresol and indole gain-of-function and loss-of-function mutants, followed by colonization of germ-free mice, and studies on host thrombosis were performed. Systemic pCS and IS levels were independently associated with all-cause mortality. Both in vitro and within colonized germ-free mice p-cresol productions were recapitulated by collaboration of two organisms: a Bacteroides strain that converts tyrosine to 4-hydroxyphenylacetate, and a Clostridium strain that decarboxylates 4-hydroxyphenylacetate to p-cresol. We then engineered a single organism, Bacteroides thetaiotaomicron, to produce p-cresol, indole, or both metabolites. Colonizing germ-free mice with engineered strains, we show the gut microbial genes for p-cresol (hpdBCA) and indole (tryptophanase) are sufficient to confer a pro-thrombotic phenotype in vivo. Moreover, human fecal metagenomics analyses show that abundances of hpdBCA and tryptophanase are associated with CVD. These studies show that pCS and IS, two abundant microbiome-derived metabolites, play a broader potential role in CVD than was previously known. They also suggest that therapeutic targeting of gut microbial p-cresol- and indole-producing pathways represent rational targets for CVD.IMPORTANCEAlterations in gut microbial composition and function have been linked to numerous diseases. Identifying microbial pathways responsible for producing molecules that adversely impact the host is an important first step in the development of therapeutic interventions. Here, we first use large-scale clinical observations to link blood levels of defined microbial products to cardiovascular disease risks. Notably, the previously identified uremic toxins p-cresol sulfate and indoxyl sulfate were shown to predict 5-year mortality risks. After identifying the microbes and microbial enzymes involved in the generation of these uremic toxins, we used bioengineering technologies coupled with colonization of germ-free mice to show that the gut microbial genes that generate p-cresol and indole are sufficient to confer p-cresol sulfate and indoxyl sulfate formation, and a pro-thrombotic phenotype in vivo. The findings and tools developed serve as a critical step in both the study and targeting of these gut microbial pathways in vivo.

Dataset Information

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

Publications

A simple method for the calculation of dialysis Kt factor as a quantitative measure of removal efficiency of uremic retention solutes: Applicability to high-dialysate vs low-dialysate volume technologies.

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