A diffusion-adjusted regional blood flow model to predict solute kinetics during haemodialysis

Schneditz, Daniel; Platzer, Dieter; Daugirdas, John T.

doi:10.1093/ndt/gfp023

Cited by 53 publications

(50 citation statements)

References 24 publications

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“…As expected, the clearance was greatest for urea, which is removed from red cells as blood passes through the dialyzer. 6 Clearance values expressed in terms of the total solute concentration were lower for the normally secreted solutes and declined as the fraction of the solute bound to plasma proteins increased. A striking difference was observed when clearances were expressed in terms of the free solute concentrations.…”

Section: Resultsmentioning

confidence: 95%

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Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion

Sirich

Funk

Plummer

et al. 2014

Journal of the American Society of Nephrology

125

145

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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.

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Section: Resultsmentioning

confidence: 95%

“…Urea diffuses out of erythrocytes as blood passes through the dialyzer; with conventional treatment, the urea clearance exceeds the plasma flow rate. 6 In the native Values are mean6SD for eight hemodialysis patients. a P,0.05 for reduction ratio of total plasma concentration compared with reduction ratio of free plasma concentration.…”

Section: Discussionmentioning

confidence: 99%

Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion

Sirich

Funk

Plummer

et al. 2014

Journal of the American Society of Nephrology

125

145

View full text Add to dashboard Cite

show abstract

“…The effect of factors such as protein binding, volume of distribution, intercompartment transfer, molecular weight, and drug charges were kept constant as previously reported for healthy humans. A number of models have been reported to explain the elimination of the solutes (urea and creatinine) from the blood during hemodialysis (27)(28)(29); however, none of these models showed their applicability to predict clearance of other commonly dosed drug during HD under clinical settings. Recently Schneditz et al (27) proposed a modified regional blood flow (diffusion assisted) physiologic-based pharmacokinetic model to explain the kinetics of creatinine and urea.…”

Section: Discussionmentioning

confidence: 99%

“…A number of models have been reported to explain the elimination of the solutes (urea and creatinine) from the blood during hemodialysis (27)(28)(29); however, none of these models showed their applicability to predict clearance of other commonly dosed drug during HD under clinical settings. Recently Schneditz et al (27) proposed a modified regional blood flow (diffusion assisted) physiologic-based pharmacokinetic model to explain the kinetics of creatinine and urea. The model explains the dialysis clearance of creatinine by incorporating a delayed intracellular and extracellular equilibrium of creatinine and introducing a K d to quantify this parameter.…”

Section: Discussionmentioning

confidence: 99%

Simulation-Based Sodium Thiosulfate Dosing Strategies for the Treatment of Calciphylaxis

Singh

Derendorf

Ross

2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Calciphylaxis remains a poorly understood life-threatening disorder with limited therapeutic options. Sodium thiosulfate (STS) has reported efficacy, thought to be because solubilizing calcium deposits promote clearance by hemodialysis (HD). Lack of rigorous pharmacokinetic studies makes it problematic for determining proper STS dosing given the expanding range of dialysis prescriptions and intensities.Design, setting, participants, & measurements The purpose of this study was to determine the dosing strategies for STS during different dialysis regimens. Given reported successes using an empiric 25 g, intravenous, 3 times per week after HD, simulations were performed to predict dosing guidelines for alternative, more or less intense dialysis to produce equivalent area under the curve drug exposure. The modeled prescriptions varied HD time from 12 to 40 h/wk over three to six sessions (Q b 200 to 400 ml/min, Q d 500 to 800 ml/min), and continuous venovenous hemodialysis at low flow rates (Q b 100 to 200 ml/min, Q d 35 to 50 ml/min), using high-flux polysulfone hemofilters. ResultsSimulations showed a marked variation in STS doses depending on HD frequency and duration. Blood and dialysate flows have a less prominent effect. Assuming no residual renal function, HD prescription permutations caused the dose to vary from 72 to 245 g/wk (70-kg adult), and the simulations provide specific guidelines for clinicians. ConclusionsBased on the success reported for one STS dosing regimen and assuming area under the curve exposure of STS is proportional to its effect, pharmacokinetic simulations can be used to calculate the dose for alternative, higher or lower intensity dialysis regimens. These strategies are imperative to assure adequate treatment for this mortal disease, as well as to avoid toxicity from excess dosing.

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“…Urea is cleared at a uniquely high rate by hemodialysis because it diffuses rapidly from both red cells and plasma. 19 In the native kidney, by contrast, urea undergoes tubular reabsorption and so is cleared less rapidly than many other solutes. As a result, conventional hemodialysis provides a time-averaged urea clearance that is about one fourth of that provided by the native kidneys.…”

Section: The Behavior Of Solutes Other Than Ureamentioning

confidence: 99%

Approaches to Uremia

Meyer

Hostetter

2014

Journal of the American Society of Nephrology

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The development of dialysis was a dramatic step forward in medicine, allowing people who would soon have died because of lack of kidney function to remain alive for years. We have since found, however, that the "artificial kidney" does not live up fully to its name. Dialysis keeps patients alive but not well. Part of the residual illness that dialysis patients experience is caused by retained waste solutes that dialysis does not remove as well as native kidney function does. New means are available to identify these toxic solutes, about which we currently know remarkably little, and knowledge of these solutes would help us to improve therapy. This review summarizes our current knowledge of toxic solutes and highlights methods being explored to identify additional toxic solutes and to enhance the clearance of these solutes to improve patient outcomes.

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A diffusion-adjusted regional blood flow model to predict solute kinetics during haemodialysis

Cited by 53 publications

References 24 publications

Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion

Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion

Simulation-Based Sodium Thiosulfate Dosing Strategies for the Treatment of Calciphylaxis

Approaches to Uremia

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