The Prescription of Drugs That Inhibit Organic Anion Transporters 1 or 3 Is Associated with the Plasma Accumulation of Uremic Toxins in Kidney Transplant Recipients

André, Camille; Mernissi, Touria; Choukroun, Gabriel; Bennis, Youssef; Kamel, Saı̈d; Liabeuf, Sophie; Bodeau, Sandra

doi:10.3390/toxins14010015

Cited by 8 publications

(11 citation statements)

References 60 publications

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“…23,24 Furosemide itself has been recognized to increase the levels of several highly associated metabolites in human patients. 20 Taken together, the mechanistic concordance suggests that many identified solute levels are at least partially determined by proximal tubular organic anion clearance and therefore may be useful as functional biomarkers.…”

Section: Discussionmentioning

confidence: 87%

“…8 Furosemide in particular has long been recognized as a specific substrate for OAT1/3 both in vitro and in vivo, with apical transport provided by multidrug resistance protein 4 similar to many uremic solutes; however, most solutes will have some affinity for multiple transporters. [18][19][20][21] As such, heterogeneity of tubular transport systems likely precludes a single gold standard marker of secretory clearance.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance

et al. 2022

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BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs via secretion. Measurements or estimates of glomerular filtration rate do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography-high resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found 7 highly (>50%) protein bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance, and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile when compared to GFR. We also found 4 highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance

et al. 2022

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“…Granados et al (2021) verified that a cohort of 20 human subjects treated with probenecid had elevated levels of tryptophan-derived metabolites, including IS and kynurenine [ 111 ]. In a cohort of kidney transplant patients, André et al (2022) demonstrated that patients with a prescription of at least one drug which inhibits OAT1/OAT3 ( n = 311) had higher plasma levels of IS, PCS, and IAA, but no difference in TMAO levels compared to patients without a prescription of OAT inhibitors ( n = 92) [ 112 ]. The authors also showed a significant accumulation of PCS in patients with OAT-inhibiting drug prescriptions than in those without, even adjusting parameters for age, renal function, transplant time, and plasma albumin levels by multivariate analysis [ 112 ].…”

Section: Cell Membrane Transporters Of Uremic Toxinsmentioning

confidence: 99%

“…In a cohort of kidney transplant patients, André et al (2022) demonstrated that patients with a prescription of at least one drug which inhibits OAT1/OAT3 ( n = 311) had higher plasma levels of IS, PCS, and IAA, but no difference in TMAO levels compared to patients without a prescription of OAT inhibitors ( n = 92) [ 112 ]. The authors also showed a significant accumulation of PCS in patients with OAT-inhibiting drug prescriptions than in those without, even adjusting parameters for age, renal function, transplant time, and plasma albumin levels by multivariate analysis [ 112 ]. Together, these data indicate that drug pharmacokinetics may affect the transport of uremic toxins involving OATs, which highlights the need to understand the interaction of transporters with these drugs and the uremic toxins, especially in CKD.…”

Section: Cell Membrane Transporters Of Uremic Toxinsmentioning

confidence: 99%

The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction

Cunha

Azevedo

Falconi

et al. 2022

Toxins

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Uremic toxins are a heterogeneous group of molecules that accumulate in the body due to the progression of chronic kidney disease (CKD). These toxins are associated with kidney dysfunction and the development of comorbidities in patients with CKD, being only partially eliminated by dialysis therapies. Importantly, drugs used in clinical treatments may affect the levels of uremic toxins, their tissue disposition, and even their elimination through the interaction of both with proteins such as albumin and cell membrane transporters. In this context, protein-bound uremic toxins (PBUTs) are highlighted for their high affinity for albumin, the most abundant serum protein with multiple binding sites and an ability to interact with drugs. Membrane transporters mediate the cellular influx and efflux of various uremic toxins, which may also compete with drugs as substrates, and both may alter transporter activity or expression. Therefore, this review explores the interaction mechanisms between uremic toxins and albumin, as well as membrane transporters, considering their potential relationship with drugs used in clinical practice.

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“…A few studies have shown that the inhibition of OAT1/OAT3 transporters (whether renal or neuronal) induces the accumulation of UTs [7,8,12]. For example, an in vivo study in rats demonstrated that the administration of ciprofloxacin decreased the renal clearance of IS [13].…”

Section: Introductionmentioning

confidence: 99%

Proton-Pump Inhibitors and Serum Concentrations of Uremic Toxins in Patients with Chronic Kidney Disease

Chamieh

Larabi

Laville

et al. 2023

Toxins

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Use of proton-pump inhibitors (PPIs) is common in patients with chronic kidney disease (CKD). PPIs and many uremic toxins (UTs) are eliminated by the kidney’s tubular organic anion transporter system. In a cross-sectional study, we sought to evaluate the association between PPI prescription and serum concentrations of various UTs. We studied a randomly selected sub-group of participants in the CKD-REIN cohort (adult patients with a confirmed diagnosis of CKD and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) with available frozen samples collected at baseline. PPI prescription was recorded at baseline. Serum concentrations of 10 UTs were measured using a validated liquid chromatography tandem mass spectrometry technique. Multiple linear regression was performed, with the log UT concentration as the dependent variable. Of the 680 included patients (median age: 68 years; median eGFR: 32 mL/min/1.73 m2), 31% had PPI prescriptions at baseline. Patients using PPIs had higher levels of certain UTs in comparison to other patients, including total and free indoxyl sulfate (IS), total and free p-cresylsulfate, total and free p-cresylglucuronide (PCG), phenylacetylglutamine (PAG), free kynurenine, and free hippuric acid. After adjustment for baseline co-morbidities, number of co-prescribed drugs, and laboratory data, including eGFR, associations between PPI prescription and elevated serum concentrations of free and total IS, free and total PCG, and PAG remained significant. Our results indicate that PPI prescription is independently associated with serum UT retention. These findings are interesting to better understand the factors that may modulate serum UT concentration in CKD patients, however, they will need to be confirmed by longitudinal studies.

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The Prescription of Drugs That Inhibit Organic Anion Transporters 1 or 3 Is Associated with the Plasma Accumulation of Uremic Toxins in Kidney Transplant Recipients

Cited by 8 publications

References 60 publications

Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance

Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance

The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction

Proton-Pump Inhibitors and Serum Concentrations of Uremic Toxins in Patients with Chronic Kidney Disease

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