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102


The Evolving View of Uremic Toxicity

Meijers, Bjorn; Lowenstein, Jerome
Indoxyl sulfate, closely related to indigo, a dye valued for it binding to cloth, has been recognized as a protein-bound solute bound to albumin, present in increased concentration in the serum of patients with impaired glomerular filtration (13). The early studies of Niwa identified indoxyl sulfate as a toxin capable of accelerating the rate of renal damage in subtotal nephrectomized rats (18). Over the past decade other protein-bound solutes have been identified in the plasma of patients with impaired glomerular filtration. Although the early studies, focused on the kidney, identified indoxyl sulfate as a toxic waste product dependent on the kidney for its removal, subsequent observations have identified organic anion transporters on many non-renal tissue, leading to the view that indoxyl sulfate is part of a systemic signaling system.
PMCID:9031373
PMID: 35448883
ISSN: 2072-6651
CID: 5205332

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence

Evenepoel, Pieter; Meijers, Bjorn; Masereeuw, Rosalinde; Lowenstein, Jerome
Sodium-glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.
PMCID:8954461
PMID: 35324707
ISSN: 2072-6651
CID: 5200612

Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes

Nazzal, Lama; Soiefer, Leland; Chang, Michelle; Tamizuddin, Farah; Schatoff, Daria; Cofer, Lucas; Aguero-Rosenfeld, Maria E; Matalon, Albert; Meijers, Bjorn; Holzman, Robert; Lowenstein, Jerome
Introduction/UNASSIGNED:Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. Methods/UNASSIGNED:We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. Results/UNASSIGNED:. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. Conclusions/UNASSIGNED:We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.
PMCID:8343810
PMID: 34386661
ISSN: 2468-0249
CID: 4966092

Uremic Toxins in Organ Crosstalk

Lowenstein, Jerome; Nigam, Sanjay K
Many putative uremic toxins-like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF-are organic anions. Both inter-organ and inter-organismal communication are involved. For example, the gut microbiome is the main source of indole, which, after modification by liver drug metabolizing enzymes (DMEs), becomes indoxyl sulfate. Various organic anion transporters (organic anion transporters, OATs; organic anion-transporting polypeptides, OATPs; multidrug resistance-associated proteins, MRPs, and other ABC transporters like ABCG2)-often termed "drug transporters"-mediate movement of uremic toxins through cells and organs. In the kidney proximal tubule, critical roles for OAT1 and OAT3 in regulating levels of protein-bound uremic toxins have been established using knock-out mice. OATs are important in maintaining residual tubular function in chronic kidney disease (CKD); as CKD progresses, intestinal transporters like ABCG2, which extrude urate and other organic anions into the gut lumen, seem to help restore homeostasis. Uremic toxins like indoxyl sulfate also regulate signaling and metabolism, potentially affecting gene expression in extra-renal tissues as well as the kidney. Focusing on the history and evolving story of indoxyl sulfate, we discuss how uremic toxins appear to be part of an extensive "remote sensing and signaling" network-involving so-called drug transporters and drug metabolizing enzymes which modulate metabolism and signaling. This systems biology view of uremic toxins is leading to a new appreciation of uremia as partly due to disordered remote sensing and signaling mechanisms-resulting from, and causing, aberrant inter-organ (e.g., gut-liver- kidney-CNS) and inter-organismal (e.g., gut microbiome-host) communication.
PMCID:8085272
PMID: 33937275
ISSN: 2296-858x
CID: 4886462

The renal transport of hippurate and protein-bound solutes

Kumar, Rohit; Adiga, Avinash; Novack, Joshua; Etinger, Alex; Chinitz, Lawrence; Slater, James; de Loor, Henriette; Meijers, Bjorn; Holzman, Robert S; Lowenstein, Jerome
Measurement of the concentration of hippurate in the inferior vena cava and renal blood samples performed in 13 subjects with normal or near-normal serum creatinine concentrations confirmed the prediction that endogenous hippurate was cleared on a single pass through the kidney with the same avidity as that reported for infused para-amino hippurate. This suggests that a timed urine collection without infusion would provide a measure of effective renal plasma flow. Comparison of the arteriovenous concentration differences for a panel of protein-bound solutes identified solutes that were secreted by the renal tubule and solutes that were subjected to tubular reabsorption.
PMCID:7041931
PMID: 32097533
ISSN: 2051-817x
CID: 4324292

Hippurate clearance provides a measure of renal plasma flow [Meeting Abstract]

Rohit, K; Adiga, A G; Etinger, A; Lowenstein, J
Background: Prior to the introduction of eGFR in 1999, glomerular filtration rate and renal plasma flow were assessed by measuring the plasma clearances of inulin and para-amino hippurate. As this required constant infusion, timed urine collection and aspecialized laboratory, these measures were not widely available. Data available from the period identified a number of clinical disorders in which the ratio of GFR to renal plasma flow (Filtration Fraction) varied considerably. Filtration fraction was known to vary considerably in different clinical states. With the introduction of eGFR, renal plasma flow is no longer measured and renal function is judged solely by eGFR. With the recognition that endogenous hippurate was transported by OATs in the proximal tubule, we undertook studies to determine whether the clearance of hippurate would present a means of estimating renal plasma flow.
Method(s): Studies were carried out in 5 subjects with hypertrophic cardiomyopathy under going right heart catheterization and 10 subjects undergoing electrophysiologic studies. Blood samples were obtained from the right renal vein and the IVC below the renal veins. A voided urine was collected 1-3 hours before blood sampling. Eight patients were receiving beta-blockers, two were receiving ACE inhibitors. Hippurate was measured utilizing MS-HPLC. Creatinine was measured by colorimetric technique.
Result(s): Among the 15 subjects, extractionof hippurate(IVC-RV/IVC) was .935 and .909 in two, from .739 to .58 in six. In the remaining seven subjects the findings suggested the RV catheter was not in the renal vein or the blood collected was an admixture of renal vein and IVC blood. The clearance ratio(U/Phippurateto U/P creatinine) was evaluated in 12 subjects; it ranged from 7.05 to 1.64 and exceeded 4 in five of the subjects studied.
Conclusion(s): The renal clearance of hippurate exceeded creatinine clearance in all subjects studied. Hippurate/creatinine clearance ratios greater than 4 suggests that hippurate clearance provides a measure of RPF. Ratios below 4.0 may reflect reduced renal plasma flow in some of the patients, who were studied during evaluation of either hypertrophic cardiomyopathy or cardiac arrhythmias. Reduced cardiac output or other medications may have reduced renal blood flow
EMBASE:633771614
ISSN: 1533-3450
CID: 4754912

The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes

Etinger, Aleksey; Kumar, Sumit; Ackley, William; Soiefer, Leland; Chun, Jonathan; Singh, Prabjhot; Grossman, Eric; Matalon, Albert; Holzman, Robert S; Meijers, Bjorn; Lowenstein, Jerome
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/CONCLUSIONS: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.
PMCID:5823377
PMID: 29470534
ISSN: 1932-6203
CID: 2964022

Correction: The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes [Correction]

Etinger, Aleksey; Kumar, Sumit R; Ackley, William; Soiefer, Leland; Chun, Jonathan; Singh, Prabjhot; Grossman, Eric; Matalon, Albert; Holzman, Robert S; Meijers, Bjorn; Lowenstein, Jerome
[This corrects the article DOI: 10.1371/journal.pone.0192770.].
PMCID:6047821
PMID: 30011331
ISSN: 1932-6203
CID: 3217952

Effect of vancomycin on plasma concentration of uremic solutes [Meeting Abstract]

Soiefer, L R; Chang, M; Tamizuddin, F; Schatoff, D; Cofer, L; Matalon, A; Nazzal, L; Meijers, B; Holzman, R; Lowenstein, J
Background: Many uremic retention solutes are products of gut bacterial metabolism. Protein-binding renders these solutes poorly dialyzable. In a prior study we observed that a single dose of 250 mg of vancomycin, given by mouth, resulted in a significant (40%) decrease in the plasma concentration of indoxyl sulfate and p-cresyl sulfate over a period of one week. In this study we compared the changes in plasma concentration of a panel of protein-bound uremic retention solutes in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 8 weeks.
Method(s): Eight subjects with chronic, stable ESRD on thrice-weekly hemodialysis via AV fistula in the River Renal Dialysis Unit in Bellevue Hospital, were randomized to two groups, utilizing a single-blinded procedure. Baseline plasma samples were collected prior to the initial dose of vancomycin or placebo and at weeks one, two, three, four, and eight. Uremic retention solutes were measured by MS-HPLC.
Result(s): Six of the eight uremic retention solutes (Table 1) demonstrated a significant decline in concentration over the eight week period of once-weekly vancomycin administration. The magnitude of the decline makes it more likely that gut production was reduced rather than renal excretion increased. Solute concentrations remained unchanged over the same period of placebo administration.
Conclusion(s): The significant decline in the plasma concentrations of multiple uremic retention solutes provides evidence of the importance of the gut microbiome in the generation of these solutes. The reduction in concentrations of indoxyl sulfate, p-cresyl sulfate, and kynurenic acid, recognized as likely uremic toxins, suggests that altering the gut microbiome might provide a valuable therapeutic strategy in the management of ESRD
EMBASE:633734138
ISSN: 1533-3450
CID: 4755842

Renal and dialytic clearances of uremic solutes [Meeting Abstract]

Lowenstein, J; Etinger, A; Slater, J; Meijers, B; Holzman, R
Background: Many uremic solutes are protein bound and removed by proximal tubular organic anion transporters (OATs) rather than filtration.
Method(s): In 4 subjects undergoing right heart catheterization, samples were obtained from the right renal vein and the inferior vena cava below the renal veins.Total and ultrafiltrate concentrations of uremic solutes were measured utilizing MS-HPLC.
Result(s): Renal extraction ratio (removal across the renal vascular bed) and renal excretion fraction (renal clearance of solute relative to creatinine) varied greatly. HA and PAG exhibited the highest renal extraction ratios and excretion fractions approximating values reported for para-amino-hippurate (PAH). The dialytic clearance of these solutes exhibited the same pattern but never exceeded estimated creatinine clearance. Highly bound solutes (IS, PCS) exhibited low renal extraction and low renal excretion fractions. KA was an anomaly. Though highly bound, renal extraction and excretion were higher than expected, possibly related to pKa or other unique properties of this solute.
Conclusion(s): The findings suggest that endogenous hippurate clearance might provide a measure of effective renal plasma flow. The finding that uremic retention solutes such as IS, PCS, and KA, known to bind to OAT receptors on vascular endothelium where they act as transcription factors, are also tightly bound to albumin suggests that protein binding serves to deliver solutes to receptors in a manner analogous to the delivery of hormones, bound to carrier proteins, from an endocrine source to distant receptors
EMBASE:633733782
ISSN: 1533-3450
CID: 4755862