Impaired Tubular Secretion of Organic Solutes in Advanced CKD

2021 ◽  
pp. ASN.2021030336
Author(s):  
Robert Mair ◽  
Seolhyun Lee ◽  
Natalie Plummer ◽  
Tammy Sirich ◽  
Timothy Meyer
Keyword(s):  
Chronic Kidney Disease ◽  
Filtration Rate ◽  
Tubular Secretion ◽  
Indoxyl Sulfate ◽  
Organic Solutes ◽  
Plasma Samples ◽  
Considerable Variability ◽  
Metabolomic Analysis ◽  
Estimated Gfr ◽  
Fractional Clearance

Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the glomerular filtration rate (GFR) in chronic kidney disease (CKD). Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. Methods To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 CKD patients with an estimated GFR of 7±2 ml/min per 1.73m2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in CKD patients and to those of creatinine in controls. Results Metabolomic analysis identified 39 secreted solutes with fractional clearance >3.0 in control participants. Fractional clearance values in CKD patients were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p-cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for CKD patients, P<0.001), p-cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for CKD patients, P<0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8, P<0.001), but not for hippurate (10.2±3.8 versus 8.4±2.6, P=0.13). Conclusions Secretory clearances for many solutes are reduced more relative to the reduction in GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.

scholarly journals Agreement and Precision Analyses of Various Estimated Glomerular Filtration Rate Formulae in Cancer Patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wiwat Chancharoenthana ◽  
Salin Wattanatorn ◽  
Somratai Vadcharavivad ◽  
Somchai Eiam-Ong ◽  
Asada Leelahavanichkul
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Cancer Patients ◽  
Filtration Rate ◽  
Estimated Glomerular Filtration Rate ◽  
Estimated Gfr ◽  
Anti Cancer ◽  
Precision And Accuracy ◽  
Racial Factor

AbstractThe accuracy of the estimated glomerular filtration rate (eGFR) in cancer patients is very important for dose adjustments of anti-malignancy drugs to reduce toxicities and enhance therapeutic outcomes. Therefore, the performance of eGFR equations, including their bias, precision, and accuracy, was explored in patients with varying stages of chronic kidney disease (CKD) who needed anti-cancer drugs. The reference glomerular filtration rate (GFR) was assessed by the 99mTc-diethylene triamine penta-acetic acid (99mTc-DTPA) plasma clearance method in 320 patients and compared with the GFRs estimated by i) the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, ii) the unadjusted for body surface area (BSA) CKD-EPI equation, iii) the re-expressed Modification of Diet in Renal Disease (MDRD) study equation with the Thai racial factor, iv) the Thai eGFR equation, developed in CKD patients, v) the 2012 CKD-EPI creatinine-cystatin C, vi) the Cockcroft-Gault formula, and vii) the Janowitz and Williams equations for cancer patients. The mean reference GFR was 60.5 ± 33.4 mL/min/1.73 m2. The bias (mean error) values for the estimated GFR from the CKD-EPI equation, BSA-unadjusted CKD-EPI equation, re-expressed MDRD study equation with the Thai racial factor, and Thai eGFR, 2012 CKD-EPI creatinine-cystatin-C, Cockcroft-Gault, and Janowitz and Williams equations were −2.68, 1.06, −7.70, −8.73, 13.37, 1.43, and 2.03 mL/min, respectively, the precision (standard deviation of bias) values were 6.89, 6.07, 14.02, 11.54, 20.85, 10.58, and 8.74 mL/min, respectively, and the accuracy (root-mean square error) values were 7.38, 6.15, 15.97, 14.16, 24.74, 10.66, and 8.96 mL/min, respectively. In conclusion, the estimated GFR from the BSA-unadjusted CKD-EPI equation demonstrated the least bias along with the highest precision and accuracy. Further studies on the outcomes of anti-cancer drug dose adjustments using this equation versus the current standard equation will be valuable.

On the Basis of Race: The Utility of a Race Factor in Estimating Glomerular Filtration

2020 ◽  
Author(s):  
Caroline E Franks ◽  
Mitchell G Scott
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Gold Standard ◽  
Filtration Rate ◽  
Routine Clinical Practice ◽  
Kidney Dysfunction ◽  
Estimated Gfr ◽  
Gold Standard Method ◽  
Estimation Equations

Abstract Background Glomerular filtration rate (GFR) is a measure of the combined rate of filtration of all functional nephrons in the kidney. Measurement of GFR is used in the clinic to detect, stratify, and monitor progression of kidney dysfunction, and also serves as a prognostic tool for staging chronic kidney disease (CKD). The gold standard method for measuring GFR is by plasma or urine clearance of exogenous filtration markers, but this is not feasible in routine clinical practice. The most commonly used method to assess GFR is using equations for estimated GFR (eGFR). Content Addition of a race factor to eGFR equations has been recommended to optimize performance for Black individuals. Here, we review the basis of the race-based equation and assess its utility and widespread applicability. Summary Although evidence supporting the performance of a race factor exists in the unique populations in which these estimation equations were derived, more studies are needed to assess the need, or lack thereof, for race factors for all ethnicities. Furthermore, ethnicity is complex and likely cannot be qualified with a 2-level descriptor.

Performance of creatinine-based equations for estimating glomerular filtration rate changes over time

2018 ◽  
Vol 35 (5) ◽  
pp. 819-827 ◽  
Author(s):  
Marieke H C van Rijn ◽  
Marie Metzger ◽  
Martin Flamant ◽  
Pascal Houillier ◽  
Jean-Philippe Haymann ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Patient Characteristics ◽  
Estimated Gfr ◽  
Changes Over Time ◽  
Over Time ◽  
Measured Gfr

Abstract Background Glomerular filtration rate (GFR) is commonly used to monitor chronic kidney disease (CKD) progression, but its validity for evaluating kidney function changes over time has not been comprehensively evaluated. We assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis. Methods In the NephroTest cohort study, we measured GFR 5324 times by chromium 51–labeled ethylenediamine tetraacetic acid renal clearance in 1955 adult patients with CKD Stages 1–4 referred to nephrologists (Stages 1–2, 19%) and simultaneously estimated GFR with both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations for isotope dilution mass spectrometry traceable creatinine; absolute and relative GFR slopes were calculated using a linear mixed model. Results Over a median follow-up of 3.4 [interquartile range (IQR) 2.0–5.6] years, the decline in mean absolute and relative measured GFR (mGFR) and CKD-EPI and MDRD estimated GFR (eGFR) was 1.6 ± 1.2, 1.5 ± 1.4 and 1.3 ± 1.3 mL/min/1.73 m2/year and 5.9 ± 5.3, 5.3 ± 5.3 and 4.8 ± 5.2%/year, respectively; 52% and 55% of the patients had MDRD and CKD-EPI eGFR slopes within 30% of mGFR slopes. Both equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and mGFR versus eGFR slope. Other patient characteristics and specific CKD diagnoses had little effect on the performance of the equations in estimating associations. Conclusions This study shows little bias, but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. Importantly, bias strongly varied with age, possibly due to variations in muscle mass over time, with implications for clinical care and research.

Chronic kidney disease

2010 ◽  
pp. 3904-3929
Author(s):  
Eberhard Ritz ◽  
Tilman B. Drüeke
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Kidney Damage ◽  
Estimated Gfr

Definition—chronic kidney disease (CKD) is defined as kidney damage lasting for more than 3 months characterized by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR). Staging—CKD has been subdivided into five stages depending on the estimated GFR (eGFR), as described in ...

scholarly journals Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 635 ◽  
Author(s):  
Caroline C. Pelletier ◽  
Mikael Croyal ◽  
Lavinia Ene ◽  
Audrey Aguesse ◽  
Stephanie Billon-Crossouard ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Renal Excretion ◽  
Plasma Concentrations ◽  
Tubular Secretion ◽  
Renal Elimination ◽  
Renal Handling

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.

scholarly journals Evaluation of CKD-EPI and MDRD Prediction Equations for Estimation of GFR in Lean and Obese Bangladeshi Subjects

2012 ◽  
Vol 5 (1) ◽  
pp. 207-213
Author(s):  
M. Saiedullah ◽  
S. Begum ◽  
M. R. Rahman ◽  
M. A. H. Khan ◽  
S. Hayat ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Kidney Disease ◽  
Filtration Rate ◽  
Obese Group ◽  
Prediction Equations ◽  
Estimated Gfr ◽  
Disease Epidemiology ◽  
Bangladeshi Population ◽  
Lean Group ◽  
Measured Gfr

Glomerular filtration rate (GFR) is the filtrate produced by the kidneys in each minute. Chronic kidney disease epidemiology (CKD-EPI) and standardized modification of diet in renal disease (MDRD) equations are the commonly used equations to estimate GFR. Evaluation of GFR prediction equations regarding body mass index is not available in Bangladeshi population. In this study we compared estimated GFR (eGFR) with GFR measured by creatinine clearance rate (CCR) in lean and obese Bangladeshi subjects. Measured GFR were 40±21 and 45±22 ml/min/1.73m2 in lean and obese groups, respectively. Compared to measured GFR, estimated GFRs were 7.5 (p<0.0001), 5.2 (p<0.0001) ml/min/1.73m2 higher for CKD-EPI and MDRD four variables (MDRD4) equations in lean group and 6.9 (p<0.0001), 3.2 (p>0.05) ml/min/1.73 m2 higher for CKD-EPI and MDRD4 equations in obese group. The precision (r2) was 0.6461 for CKD-EPI, 0.6508 for MDRD4 equations in lean group and 0.6337 for CKD-EPI and 0.6021 for MDRD4 equations in obese group. The percentages of eGFR falling within 15% measured GFR were 37 for CKD-EPI, 52 for MDRD4 in lean group; 41 for CKD-EPI, 39 for MDRD4 in obese group. CKD-EPI equation overestimates GFR in both lean and obese, but MDRD4 equation overestimates GFR only in lean Bangladeshi subjects.© 2013 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi: http://dx.doi.org/10.3329/jsr.v5i1.8764          J. Sci. Res. 5 (1), 207-213 (2013)

scholarly journals The Source and Pathophysiologic Significance of Excreted Cadmium

Toxics ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 55 ◽  
Author(s):  
Soisungwan Satarug ◽  
David A. Vesey ◽  
Werawan Ruangyuttikarn ◽  
Muneko Nishijo ◽  
Glenda C. Gobe ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Filtration Rate ◽  
Cellular Damage ◽  
Tubular Injury ◽  
Estimated Gfr ◽  
Tubular Cells ◽  
Thai Subjects ◽  
Urine Concentrations ◽  
Excretion Rates ◽  
Cd Exposure

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]u); and β2-microglobulin, an indicator of reabsorptive dysfunction ([β2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eβ2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eβ2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

scholarly journals Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury

Kidney360 ◽  
2020 ◽  
Vol 1 (8) ◽  
pp. 724-730
Author(s):  
Frank J. O’Brien ◽  
Robert D. Mair ◽  
Natalie S. Plummer ◽  
Timothy W. Meyer ◽  
Scott M. Sutherland ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Plasma Levels ◽  
Kidney Injury ◽  
Tubular Secretion ◽  
Organic Solutes ◽  
Total Plasma ◽  
Spot Urine ◽  
Fractional Clearance ◽  
Organic Solute ◽  
Free Plasma

BackgroundImpairment of kidney function is routinely assessed by measuring the accumulation of creatinine, an organic solute cleared largely by glomerular filtration. We tested whether the clearance of solutes that undergo tubular secretion is reduced in proportion to the clearance of creatinine in humans with AKI.MethodsFour endogenously produced organic solutes (phenylacetylglutamine [PAG], hippurate [HIPP], indoxyl sulfate [IS], and p-cresol sulfate [PCS]) were measured in spot urine and plasma samples from ten patients with AKI and 17 controls. Fractional clearance relative to creatinine was calculated to assess tubular secretion. Fractional clearance values were calculated in terms of the free, unbound levels of HIPP, IS, and PCS that bind to plasma proteins.ResultsFractional clearance values for PAG, HIPP, IS, and PCS were >1.0 in patients with AKI as well as controls, indicating that these solutes were still secreted by the tubules of the injured kidneys. Fractional clearance values were, however, significantly lower in patients with AKI than controls, indicating that kidney injury reduced tubular secretion more than glomerular filtration (AKI versus control: PAG, 2.1±0.7 versus 4.6±1.4, P<0.001; HIPP, 10±5 versus 15±7, P=0.02; IS, 10±6 versus 28±7, P<0.001; PCS, 3.3±1.8 versus 10±3, P<0.001). Free plasma levels rose out of proportion to total plasma levels for each of the bound solutes in AKI, so that calculating their fractional clearance in terms of their total plasma levels failed to reveal their impaired secretion.ConclusionsTubular secretion of organic solutes can be reduced out of proportion to glomerular filtration in AKI. Impaired secretion of protein-bound solutes may be more reliably detected when clearances are expressed in terms of their free, unbound levels in the plasma.

Observations from a teaching hospital in Ireland: changing from MDRD to CKD-EPI eGFR in routine practice

2020 ◽  
pp. jclinpath-2020-206713
Author(s):  
Janice Lee Veronica Reeve ◽  
Marion Davis ◽  
Patrick Joseph Twomey
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Filtration Rate ◽  
Clinical Chemistry ◽  
Routine Practice ◽  
Estimated Gfr ◽  
Ckd Stage ◽  
Service Application ◽  
Improved Accuracy ◽  
Older Males

Estimates of glomerular filtration rate (eGFR) help assess kidney function. Estimated GFR can be used to classify patients into one of six Chronic Kidney Disease (CKD) categories as recommended by the Kidney Disease Improving Global Outcomes clinical practice guidelines; CKD1 ≥90, CKD2 60–89, CKD3a 45–59, CKD3b 30–44, CKD4 15–29 or CKD5 ≤15 mL/min/1.73 m2. The Modification of Diet and Renal Disease (MDRD) study formula was widely adopted to calculate eGFR. The CKD Epidemiology Collaboration (CKD-EPI) formula improved accuracy of CKD staging at eGFR ≥60 mL/min/1.73 m2. MDRD and CKD-EPI eGFR were calculated on 111 444 serum creatinine results from adult patients measured as part of the routine Clinical Chemistry service. Application of CKD-EPI eGFR reclassified 18% to a lower (13.9%) or higher (4.0%) CKD stage. CKD staging was lower when <65 years and higher when ≥65 years. Females were more often reclassified compared with males (2.6% vs 0.8%). Overall, CKD-EPI eGFR classified less with CKD (stages 3a-5), unless ≥75 years. Older males and inpatients had higher CKD stages when CKD-EPI eGFR was applied. It has been recommended to replace MDRD eGFR with CKD-EPI eGFR. In general, doing this will have little impact, however, for some patients their CKD classification will be different.

Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone

2011 ◽  
Vol 300 (4) ◽  
pp. F830-F837 ◽  
Author(s):  
Donald E. Wesson ◽  
Jan Simoni ◽  
Kristine Broglio ◽  
Simon Sheather
Keyword(s):  
Chronic Kidney Disease ◽  
Metabolic Acidosis ◽  
Plasma Levels ◽  
Filtration Rate ◽  
Mineralocorticoid Receptors ◽  
Acid Excretion ◽  
Vascular Effects ◽  
Estimated Gfr ◽  
Ckd Stage ◽  
Gfr Decline

Dietary alkali slows GFR decline in humans with a moderately reduced glomerular filtration rate (GFR) despite the absence of metabolic acidosis. Similarly, dietary alkali slows GFR decline in animals with 2/3 nephrectomy (Nx), a chronic kidney disease (CKD) model without metabolic acidosis in which GFR decline is mediated by acid (H+) retention through endothelin (ET) and mineralocorticoid receptors. To gain insight as to whether this mechanism might mediate GFR decline in humans, we explored whether macroalbuminuric subjects with moderately reduced (CKD stage 2 = 60–90 ml/min; CKD 2) compared with normal estimated GFR (>90 ml/min; CKD 1), each without metabolic acidosis, have H+ retention that increases plasma levels of ET-1 and aldosterone. Baseline plasma ET and aldosterone concentrations were each higher in CKD 2 than CKD 1. Baseline dietary H+ and urine net acid excretion (NAE) were not different between groups, but an acute oral NaHCO3 bolus reduced urine NAE less (i.e., postbolus urine NAE was higher) in CKD 2 than CKD 1, consistent with greater H+ retention in CKD 2 subjects. Thirty days of oral NaHCO3 reduced H+ retention in CKD 2 but not CKD 1 subjects and reduced plasma ET and aldosterone in both groups but to levels that remained higher in CKD 2 for each. Subjects with CKD stage 2 eGFR and no metabolic acidosis nevertheless have H+ retention that increases plasma ET and aldosterone levels, factors that might mediate subsequent GFR decline and other untoward vascular effects.

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