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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

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

The effect of isohydric hemodialysis on uremic retention solutes [Meeting Abstract]

Lowenstein, J; Etinger, A; Kumar, S R; Ackley, W; Soiefer, L R; Grossman, E B; Matalon, A; Holzman, R; Meijers, B
Background: There is growing evidence that the accumulation of protein-bound uremic retention solutes, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS) and kynurenic acid (KA), 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 had previously observed that the concentration of free solute and its unbound fraction were markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and the changes attributable to the higher serum pH at the end of hemodialysis. In vitro, acidification of uremic plasma to pH 6 greatly increased the proportion of unbound indoxyl sulfate.
Method(s): We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mEq/L for the initial half of hemodialysis ('isohydric dialysis'). Eight stable hemodialysis patients underwent 'isohydric dialysis' and, midway, were switched to standard buffer (37 mEq/L). A second dialysis, 2 days later, employed standard buffer throughout.
Result(s): We found a clearcut separation of blood pH and bicarbonate concentrations 90 minutes following 'isohydric dialysis' (pH = 7.37, HCO3 =22.4 mEq/l) and standard dialysis (pH= 7.49, HCO3 = 29.5). Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in 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.
Conclusion(s): These findings suggest that modification of dialysis technique that would expose blood to a transient decrease in pH might increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of protein-bound uremic retention solutes
EMBASE:633701643
ISSN: 1533-3450
CID: 4750422

Uremic Retention Solutes

Chapter by: Ackley, William; Soiefer, Leland; Etinger, Aleksey; Lowenstein, Jerome
in: Aspects of dialysis by Karkar, Ayman (Ed)
pp. -
ISBN: 978-1-78923-025-3
CID: 5241142