Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate

BackgroundAlthough proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR.MethodsIn a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances.ResultsMedian iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir.ConclusionsSecretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.

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Proximal Tubular Secretory Clearance

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.12001017 ◽

2018 ◽

Vol 13 (8) ◽

pp. 1291-1296 ◽

Cited By ~ 30

Author(s):

Ke Wang ◽

Bryan Kestenbaum

Keyword(s):

Kidney Disease ◽

Kidney Function ◽

Clinical Care ◽

Tubular Secretion ◽

Proximal Tubules ◽

Disease Outcomes ◽

Peritubular Capillaries ◽

Proximal Tubular ◽

Homeostatic Function ◽

Solute Clearance

The secretion of small molecules by the proximal tubules of the kidneys represents a vital homeostatic function for rapidly clearing endogenous solutes and medications from the circulation. After filtration at the glomerulus, renal blood flow is directed through a network of peritubular capillaries, where transporters of the proximal tubules actively secrete putative uremic toxins and hundreds of commonly prescribed drugs into the urine, including protein-bound substances that cannot readily cross the glomerular basement membrane. Despite its central physiologic importance, tubular secretory clearance is rarely measured or even estimated in clinical or research settings. Major barriers to estimating tubular solute clearance include uncertainty regarding optimal endogenous secretory markers and a lack of standardized laboratory assays. The creation of new methods to measure tubular secretion could catalyze advances in kidney disease research and clinical care. Differences in secretory clearance relative to the GFR could help distinguish among the causes of CKD, particularly for disorders that primarily affect the tubulointerstitium. As the primary mechanism by which the kidneys excrete medications, tubular secretory clearance offers promise for improving kidney medication dosing, which is currently exclusively on the basis of filtration. The differing metabolic profiles of retained solutes eliminated by secretion versus glomerular filtration suggest that secretory clearance could uniquely inform uremic toxicity, refine existing measures of residual kidney function, and improve prediction of cardiovascular and kidney disease outcomes. Interdisciplinary research across clinical, translational, and laboratory medicine is needed to bring this often neglected kidney function into the limelight.

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Differences in proximal tubular solute clearance across common etiologies of chronic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz144 ◽

2019 ◽

Vol 35 (11) ◽

pp. 1916-1923 ◽

Cited By ~ 2

Author(s):

Ke Wang ◽

Leila R Zelnick ◽

Andrew N Hoofnagle ◽

Yan Chen ◽

Ian H de Boer ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vascular Disease ◽

Tubular Secretion ◽

Urine Concentration ◽

Glomerular Function ◽

Urine Albumin ◽

Proximal Tubular ◽

Paired Serum ◽

Solute Clearance

AbstractBackgroundLaboratory measures of glomerular function such as the glomerular filtration rate (GFR) contribute toward clinical evaluation of chronic kidney disease (CKD). However, diverse CKD etiologies have distinct pathological mechanisms that may differentially impact the kidney tubules. Little is known regarding how tubular function changes with varying kidney disease types.MethodsWe used targeted mass spectrometry to quantify paired serum and urine concentration of 11 solutes of proximal tubular secretion in 223 patients from an outpatient CKD cohort. We reviewed clinic notes to ascertain the primary CKD diagnosis and categorized these as vascular, diabetic, glomerular or tubulointerstitial. We used one-way analysis of variance to compare secretory solute clearance across diagnoses setting a false discovery threshold of ≤5% and used linear regression to compare differences after adjustments for estimated GFR, age, race, sex, body mass index and urine albumin excretion.ResultsAfter full adjustment, glomerular disease was associated with higher clearances of three tubular secretory solutes compared with vascular disease: 48% higher isovalerylglycine clearance [95% confidence interval (CI) 18–87%], 28% higher kynurenic acid clearance (95% CI 3–59%) and 33% higher tiglylglycine clearance (95% CI 7–67%). Diabetic kidney disease (DKD) was associated with 39% higher isovalerylglycine clearance compared with vascular disease (95% CI 13–72%).ConclusionGlomerular disorders and DKD are associated with higher net clearances of several secretory solutes compared with vascular causes of kidney disease. These findings suggest that different underlying etiologies of CKD may differentially impact proximal tubular secretory pathways.

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Drug Dosing in Acute Kidney Injury

10.2310/im.12039 ◽

2017 ◽

Author(s):

Steven Gabardi ◽

Marjan Sadegh ◽

Jamil Azzi ◽

Craig A Stevens

Keyword(s):

Acute Kidney Injury ◽

Renal Dysfunction ◽

Kidney Injury ◽

Drug Clearance ◽

Tubular Secretion ◽

Drug Dosing ◽

Drug Concentrations ◽

Individualized Dosing ◽

Altered Pharmacokinetic ◽

Pharmacologic Agents

The prevalence of acute kidney injury (AKI) among hospitalized patients has increased sharply over the past 10 to 20 years. One complicating factor in this population is that many pharmacologic agents that are administered to these patients are handled, to some degree, by the kidneys. These medications may experience altered pharmacokinetic and pharmacodynamic profiles in patients with renal dysfunction, increasing the chances of drug misadventures. Historically, drug dosing in patients with AKI has been approached in the same manner as in patients with chronic renal insufficiency (CRI). The majority of dosing recommendations for AKI have been extrapolated from studies performed in patients with stable CRI. Renal drug clearance, composed of glomerular filtration, tubular secretion, and renal drug metabolism, is affected by renal dysfunction. It is clear that there is a reduction in renal clearance of drugs and toxins in both AKI and CRI. However, the type of renal dysfunction may affect other parameters of drug handling. Thus, dosing stratagems extrapolated from patients with CRI may result in subtherapeutic drug concentrations and ineffective treatment. Achieving a balance between under- and overdosing requires rigorous monitoring and individualized dosing. Key words: acute kidney injury, drug dosing, pharmacokinetics

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Drug Dosing in Acute Kidney Injury

10.2310/nephro.12039 ◽

2017 ◽

Author(s):

Steven Gabardi ◽

Marjan Sadegh ◽

Jamil Azzi ◽

Craig A Stevens

Keyword(s):

Acute Kidney Injury ◽

Renal Dysfunction ◽

Kidney Injury ◽

Drug Clearance ◽

Tubular Secretion ◽

Drug Dosing ◽

Drug Concentrations ◽

Individualized Dosing ◽

Altered Pharmacokinetic ◽

Pharmacologic Agents

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The dominant frequency analysis of interfacial wave in wet-gas pipeline transportation based on NIR absorption

Journal of Intelligent & Fuzzy Systems ◽

10.3233/jifs-219072 ◽

2021 ◽

pp. 1-10

Author(s):

Zhiyue Zhao ◽

Ning Zhao ◽

Lide Fang ◽

Xiaoting Li

Keyword(s):

Liquid Film ◽

Predictive Accuracy ◽

Film Surface ◽

Dominant Frequency ◽

Wave Frequency ◽

Interfacial Wave ◽

Long Distance ◽

Wet Gas ◽

The Mean ◽

Predictive Correlation

During the long-distance transportation of wet-gas, the dominant frequency is of great significance for the study of pipeline fatigue and damage, and the safety production. Therefore, the theoretical and experimental researches for dominant frequency are carried out increasingly. However, most of the current prediction correlation of dominant frequency are mainly applicable to atmospheric pressure conditions (0.1 MPa), and the prediction accuracy is not accurate enough. The paper obtains the time series signal of liquid film thickness by near-infrared (NIR) sensor, and then calculates the wave frequency by the power spectrum density (PSD). The performance of typical predictive correlation is evaluated and analyzed by utilizing the experimental data at different flow and pressure conditions (0.1–0.8) MPa. The structure of Strouhal number and Lockhart-Martinelli (L-M) parameter are optimized reasonably, the mean velocity of the liquid film surface, the density increment of gas core, the gas core mass flow and average liquid film velocity are considered in the L-M parameter, a modified interfacial wave frequency correlation is proposed. The results indicate that the mean absolute error of the predictive correlation is 9.06% (current data) and 25.64% (literature data). The new correlation has a better predictive accuracy.

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The predictive accuracy of hypoxic scoring for prediction of adverse outcome in neonates born with asphyxia

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20200104 ◽

2020 ◽

Vol 7 (2) ◽

pp. 333

Author(s):

Muhammad Saqib ◽

Safeer A. Jamil ◽

Usman Arif ◽

Zubda Anwar ◽

Sarosh Waheed ◽

...

Keyword(s):

Predictive Accuracy ◽

Adverse Outcome ◽

Birth Asphyxia ◽

Major Contributor ◽

Fetal Hypoxia ◽

Negative Data ◽

Term Infants ◽

Study Objective ◽

The Mean ◽

Sensitivity Specificity

Background: Birth asphyxia is a major contributor to neonatal mortality. Fetal hypoxia followed by asphyxia is common cause of brain injury in term infants. Hypoxia score has shown to be accurate enough to predict adverse outcome in asphyxiated neonates. But controversies exist regarding predictive accuracy of hypoxia score. So we conducted this study. Objective to assess the predictive accuracy of hypoxic scoring for prediction of adverse outcome in neonates born with asphyxia.Methods: 170 neonates were screed for hypoxia score. Neonates were labelled as positive or negative. Then all neonates were followed-up for 7 days. If neonate died within 7days, then case was confirmed as positive or negative. Data was analysed by using SPSS 20. 2x2 table was developed to calculate sensitivity, specificity, PPV, NPV and predictive accuracy of hypoxia score.Results: The mean Apgar score at birth was 5.01±0.83. The sensitivity of hypoxia score was 87.8%, specificity was 90.9%, PPV was 90%, NPV was 88.9% while predictive accuracy was 89.4% taking actual adverse outcome as gold standard.Conclusions: The predictive accuracy of hypoxia score was high for prediction of adverse outcome in asphyxiated neonates.

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A biochemical profile of cardiac involvement in perinatal asphyxia

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20180033 ◽

2018 ◽

Vol 5 (2) ◽

pp. 328 ◽

Cited By ~ 1

Author(s):

Senthil Kumar P. ◽

Durai Arasan G.

Keyword(s):

Creatine Kinase ◽

Cardiac Involvement ◽

Predictive Accuracy ◽

Perinatal Asphyxia ◽

P Value ◽

Perinatal Hypoxia ◽

Specific Enzyme ◽

Mortality And Morbidity ◽

Significant Difference ◽

The Mean

Background: Perinatal hypoxia is one of the leading causes of mortality and morbidity in developing countries like India, and even in developed countries. Perinatal hypoxia can result in Transient myocardial ischemia, tricuspid and mitral regurgitation, myocardial infarction, cardiac failure. The measurement of Creatine kinase -MB isoenzyme a cardiac specific enzyme helps in assessing the degree of myocardial involvement in asphyxiated infants.Methods: A Prospective case-control study was done in a Tertiary care centre serving rural areas predominantly, to determine the cardiac involvement by measuring serum MB isoenzyme of creatine kinase in perinatally asphyxiated inborn term babies for a period of six months.Results: There was a significant difference in the CK-MB values with regard to weight in both cases and controls. The mean CK-MB levels were higher in babies who had assisted delivery (forceps and breech) than those delivered by labour natural and LSCS. Mean CK-MB values of asphyxiated and controls were 133.8u/l and 27.12 u/l respectively with a p value of < 0.01. There was a significant difference between HIE1 and 3 with a p value of<0.02. Out of 60 cases 28 had abnormal ECG findings (46.6%). Statistically significant difference was found in the mean CK-MB between the normal and Grade4 ECG changes group. The overall predictive accuracy of CK-MB is high in Perinatal asphyxia (88%), Cardiac involvement (83%), Mortality (83%) and a moderate predictive accuracy for HIE (75%).Conclusions: Cardiac abnormalities in asphyxiated neonates are often underdiagnosed and requires high index of suspicion. Cardiac specific enzyme CK-MB helps in early recognition of myocardial damage and better management of cases, would reduce the neonatal mortality and morbidity. An expectant eye can be kept for complications in babies with markedly elevated CK-MB enzyme.

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Dynamics of Renal Proximal Tubular Secretion

Nature ◽

10.1038/189927a0 ◽

1961 ◽

Vol 189 (4768) ◽

pp. 927-928 ◽

Cited By ~ 13

Author(s):

FREDRIK KIIL

Keyword(s):

Tubular Secretion ◽

Proximal Tubular ◽

Renal Proximal Tubular

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Development and Validation of a UHPLC-ESI-MS/MS Method for Quantification of Oleandrin and Other Cardiac Glycosides and Evaluation of Their Levels in Herbs and Spices from the Belgian Market

Toxins ◽

10.3390/toxins12040243 ◽

2020 ◽

Vol 12 (4) ◽

pp. 243 ◽

Cited By ~ 2

Author(s):

Svetlana V. Malysheva ◽

Patrick P. J. Mulder ◽

Julien Masquelier

Keyword(s):

Cardiac Glycosides ◽

Solid Phase ◽

Plant Secondary Metabolites ◽

Naturally Occurring ◽

Relative Standard ◽

Liquid Chromatography Tandem Mass ◽

Repeatability And Reproducibility ◽

Culinary Herbs ◽

The Mean ◽

Development And Validation

Cardiac glycosides (CGs) are naturally occurring plant secondary metabolites that can be toxic to humans and animals. The aim of this work was to develop a targeted analytical method utilizing liquid chromatography—tandem mass spectrometry (LC-MS/MS) for quantification of these plant toxins in a herbal-based food and human urine. The method included oleandrin, digoxin, digitoxin, convallatoxin, and ouabain. Samples of culinary herbs were extracted with acetonitrile and cleaned using Oasis® MAX solid-phase extraction (SPE), while samples of urine were diluted with acidified water and purified on Oasis® HLB SPE cartridges. Limits of quantification were in the range of 1.5–15 ng/g for herbs and 0.025–1 ng/mL for urine. The mean recovery of the method complied with the acceptable range of 70–120% for most CGs, and relative standard deviations were at maximum 14% and 19% for repeatability and reproducibility, respectively. Method linearity was good with calculated R² values above 0.997. The expanded measurement uncertainty was estimated to be in the range of 7–37%. The LC-MS/MS method was used to examine 65 samples of culinary herbs and herb and spice mixtures collected in Belgium, from supermarkets and local stores. The samples were found to be free from the analyzed CGs.

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Accuracy of predicting the vancomycin concentration in Japanese cancer patients by the Sawchuk–Zaske method or Bayesian method

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219851834 ◽

2019 ◽

Vol 26 (3) ◽

pp. 543-548

Author(s):

Toshihisa Nakashima ◽

Takayuki Ohno ◽

Keiichi Koido ◽

Hironobu Hashimoto ◽

Hiroyuki Terakado

Keyword(s):

Cancer Patients ◽

Prediction Error ◽

Bayesian Method ◽

Predictive Accuracy ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Squared Prediction Error ◽

Trough Concentrations ◽

The Mean ◽

Mean Prediction Error

Background In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk–Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk–Zaske and Bayesian methods in Japanese cancer patients is not completely understood. Objective To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk–Zaske method and the Bayesian method in Japanese cancer patients. Methods Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Results Prediction of the trough and peak vancomycin concentrations by the Sawchuk–Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. Conclusion The Sawchuk–Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

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