scholarly journals Proximal Tubular Secretory Clearance

2018 ◽  
Vol 13 (8) ◽  
pp. 1291-1296 ◽  
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.

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

2019 ◽  
Vol 35 (11) ◽  
pp. 1916-1923 ◽  
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.

Evidence for PAH extraction from superficial cortical efferent vessel plasma

1983 ◽  
Vol 245 (5) ◽  
pp. F577-F583
Author(s):  
S. W. Weinstein ◽  
R. Klose ◽  
A. M. Kumar
Keyword(s):  
Proximal Tubule ◽  
Tubular Secretion ◽  
Proximal Convoluted Tubule ◽  
Peritubular Capillary ◽  
Blood Samples ◽  
Rapid Extraction ◽  
Peritubular Capillaries ◽  
Pars Recta ◽  
Proximal Tubular

Consistent with its anatomical association with the proximal tubule we have previously shown that superficial cortical efferent vessel blood contains an admixture of early and late proximal tubular reabsorbate. Since tubular secretion of p-aminohippurate (PAH) occurs predominantly in the late proximal tubule, extraction of this compound should occur preferentially from efferent vessel blood. As a result, the midportion of the proximal convoluted tubule supplied by the more downstream peritubular capillaries would receive blood containing a disproportionately reduced concentration of PAH. To study this, proximal and distal tubular fluid and efferent vessel blood samples were collected from rats. The data confirm that preferential secretion of PAH occurs in the pars recta and demonstrate that PAH is extracted from efferent vessel plasma by the pars recta. This in turn preferentially reduces PAH concentration in early postglomerular blood before it reaches the peritubular capillary network. We speculate that PAH and similar substances secreted by the pars recta are short-circuited by rapid extraction from early postglomerular blood, reducing their delivery to the mid-proximal convoluted tubule. Such circumstances must be considered in any analysis of organic compound secretion by the in vivo proximal tubule.

Targeted deletion of NADPH-Oxidase Nox4 from proximal tubules is dispensable for diabetic kidney disease development

2020 ◽  
Author(s):  
Vicki Thallas-Bonke ◽  
Sih Min Tan ◽  
Runa S Lindblom ◽  
Matthew Snelson ◽  
Cesare Granata ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Nadph Oxidase ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Proximal Tubules ◽  
Disease Development ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Proximal Tubular

Abstract Background The NADPH oxidase isoform, Nox4, mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in diabetic kidney disease within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. Methods We generated a proximal tubular specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the Sglt2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. Results Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of diabetic kidney disease including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKOSTZ mice compared to Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. Conclusion Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence diabetic kidney disease development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.

scholarly journals Alterations of Proximal Tubular Secretion in Autosomal Dominant Polycystic Kidney Disease

2019 ◽  
Vol 15 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Ke Wang ◽  
Leila R. Zelnick ◽  
Yan Chen ◽  
Andrew N. Hoofnagle ◽  
Terry Watnick ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Confidence Interval ◽  
Autosomal Dominant ◽  
Fractional Excretion ◽  
Tubular Secretion ◽  
Kidney Volume ◽  
Acid Excretion ◽  
Polycystic Kidney ◽  
Proximal Tubular ◽  
Autosomal Dominant Polycystic Kidney

Background and objectivesIn autosomal dominant polycystic kidney disease (ADPKD), the GFR often remains normal despite significant nephron loss. Proximal tubular secretory clearance may be reduced in ADPKD before detectable changes in GFR.Design, setting, participants, & measurementsWe used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean eGFR =111±11 ml/min per 1.73 m2) and 25 healthy control individuals as well as from 95 patients with ADPKD and reduced GFR (mean eGFR =53±21 ml/min per 1.73 m2) and 92 individuals with non-ADPKD CKD. We used linear regression to compare the fractional excretion of each solute between ADPKD and control groups. Among 112 patients with ADPKD, we used linear regression to determine associations of solute fractional excretion with height-adjusted total kidney volume.ResultsAfter adjusting for demographics, clinical characteristics, and kidney function measures, the fractional excretions of three secretory solutes were lower in patients with ADPKD and preserved GFR compared with healthy individuals: 52% lower cinnamoylglycine excretion (95% confidence interval, 24% to 70%), 53% lower tiglylglycine excretion (95% confidence interval, 23% to 71%), and 91% lower xanthosine excretion (95% confidence interval, 83% to 95%). In addition to lower excretions of tiglylglycine and xanthosine, patients with ADPKD and reduced GFR also demonstrated 37% lower dimethyluric acid excretion (95% confidence interval, 21% to 50%), 58% lower hippurate excretion (95% confidence interval, 48% to 66%), 48% lower isovalerylglycine excretion (95% confidence interval, 37% to 56%), and 31% lower pyridoxic acid excretion (95% confidence interval, 16% to 42%) compared with patients with non-ADPKD CKD and comparable eGFR. Among patients with ADPKD, solute fractional excretions were not associated with differences in kidney volume.ConclusionsPatients with ADPKD and preserved and reduced GFR demonstrate lower tubular secretory solute excretion compared with healthy controls and patients with non-ADPKD CKD. Our results suggest that tubular secretion is impaired in ADPKD independent of GFR.

Luminal hypotonicity: a driving force for fluid absorption from the proximal tubule

1984 ◽  
Vol 246 (2) ◽  
pp. F167-F174 ◽  
Author(s):  
R. Green ◽  
G. Giebisch
Keyword(s):  
Reflection Coefficient ◽  
Driving Force ◽  
Proximal Tubules ◽  
Tubular Epithelium ◽  
Fluid Absorption ◽  
Fluid Reabsorption ◽  
Hypotonic Fluid ◽  
Peritubular Capillaries ◽  
Proximal Tubular ◽  
Proximal Tubular Epithelium

The ability of rat proximal tubules to generate a hypotonic luminal fluid was investigated. Simultaneous perfusion of tubules and peritubular capillaries was performed with simple solutions. When tubules were perfused at 10 nl X min-1 and NaCl was the perfusate for tubules and capillaries, solute and fluid (0.41 nl X min-1 X mm-1) were transported and the luminal fluid became hypotonic (delta osmol = -1.7 mosmol X kg-1). When the same solutions were used but the tubule was perfused at 45 nl X min-1, more fluid (0.89 nl X min-1 X mm-1) was reabsorbed and the fluid became more hypotonic (delta osmol = -3.9 mosmol X kg-1). Bicarbonate in the peritubular capillaries increased the fluid reabsorption (1.21 nl X min-1 X mm-1) but did not generate cryoscopically hypotonic fluid. Cyanide abolished all net movement of fluid and solute. It is concluded that the tubule can generate a hypotonic fluid, that the hydraulic conductivity for proximal tubular epithelium is 3,200-3,400 microns X s-1, and that the reflection coefficient for NaHCO3 is slightly higher than for NaCl.

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

2020 ◽  
pp. ASN.2020060833
Author(s):  
Yan Chen ◽  
Leila R. Zelnick ◽  
Andrew N. Hoofnagle ◽  
Catherine K. Yeung ◽  
Laura M. Shireman ◽  
...  
Keyword(s):  
Predictive Accuracy ◽  
Drug Clearance ◽  
Tubular Secretion ◽  
Drug Elimination ◽  
Drug Dosing ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Strategies ◽  
Proximal Tubular ◽  
The Mean ◽  
Solute Clearance

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.

Functional Reserve of the Kidney

2021 ◽  
pp. CJN.11070821
Author(s):  
Armando Armenta ◽  
Magdalena Madero ◽  
Bernardo Rodriguez-Iturbe
Keyword(s):  
Kidney Disease ◽  
Tubular Secretion ◽  
Stress Tests ◽  
Functional Reserve ◽  
Normal Limits ◽  
Progression Of Kidney Disease ◽  
Proximal Tubular ◽  
History Of ◽  
The Difference

The exploration of the normal limits of physiological responses and how these responses are lost when the kidney is injured are rarely used in clinical practice. However, the difference between "resting" and the "stressed" responses identify an adaptive reactiveness that is diminished before baseline function is impaired. This functional reserve is important in the evaluation of prognosis and progression of kidney disease. Here we discuss stress tests that examine protein-induced hyperfiltration, proximal tubular secretion, urea-selective concentration defects and acid retention. We discuss diseases in which these tests have been used to diagnose subclinical injury. The study and follow-up of abnormal functional reserve may add considerable understanding to the natural history of chronic kidney disease.

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