HUMAN RENAL ORGANIC ANION TRANSPORTER 1 (hOAT1) AND ITS ROLE IN THE NEPHROTOXICITY OF ANTIVIRAL NUCLEOTIDE ANALOGS

Cihlář, Tomáš; Ho, Edmund; Lin, Deborah C.; Mulato, Andrew

doi:10.1081/ncn-100002341

Cited by 219 publications

(145 citation statements)

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“…Those include: lack of estimating toxicity of compounds that require metabolism and bioactivation by the liver, for example compounds such as acetaminophen, an analgesic with nephrotoxicity attributed to its hepatic metabolite N-acetyl-p-benzoquinone imine; lack of apical to basolateral polarity when cultured on a flat surface, which might not allow the uptake of certain antiviral drugs therefore misrepresenting its safety, for example OAT1 and OAT3, expressed at the basolateral membrane of proximal tubular epithelial cells mediating the uptake of antiviral agents tenofovir and acyclovir. 34,35 This lack of basolateral uptake of tenofovir may explain why we did not observe toxic effects in this study. Furthermore, the absence of immune or endothelial cells prevents the assessment of the nephrotoxic potential of immunologically active drugs.…”

Section: Discussionmentioning

confidence: 48%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity, but there is no high throughput in vitro method for predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells rendering them desirable to use in such in vitro systems. To identify a reliable biomarker of nephrotoxicity, we conducted multiplexed gene expression profiling of HPTECs after exposure to six different concentrations of nine human nephrotoxicants. Only overexpression of the gene encoding heme oxygenase-1 (HO-1) significantly correlated with increasing dose for six of the compounds, and significant HO-1 protein deregulation was confirmed with each of the nine nephrotoxicants. Translatability of HO-1 increase across species and platforms was demonstrated by computationally mining two large rat toxicogenomic databases for kidney tubular toxicity and by observing a significant increase in HO-1 after toxicity using an ex vivo three-dimensional microphysiologic system (kidneyon-a-chip). The predictive potential of HO-1 was tested using an additional panel of 39 mechanistically distinct nephrotoxic compounds. Although HO-1 performed better (area under the curve receiver-operator characteristic curve [AUC-ROC]=0.89) than traditional endpoints of cell viability (AUC-ROC for ATP=0.78; AUC-ROC for cell count=0.88), the combination of HO-1 and cell count further improved the predictive ability (AUC-ROC=0.92). We also developed and optimized a homogenous time-resolved fluorescence assay to allow high throughput quantitative screening of nephrotoxic compounds using HO-1 as a sensitive biomarker. This cell-based approach may facilitate rapid assessment of potential nephrotoxic therapeutics and environmental chemicals. Drugs and environmental chemicals, such as aminoglycoside antibiotics, analgesics, chemotherapeutic agents, and heavy metals, as well as endemic toxins like aristolochic acid are a common cause of AKI or CKD. 1,2 Current approaches to conduct safety and risk assessment of compounds rely predominantly on animal studies, and these results are extrapolated to dose effects in humans despite knowledge that the typical responses of animal models and humans can differ greatly. 3 The lack of adequate models to accurately predict human toxicity contributes to an underestimation of the kidney toxic potential of new therapeutic candidates, which also explains why nephrotoxic effects in patients are often only detected during late phase

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Section: Discussionmentioning

confidence: 48%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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“…The mechanism underlying this complication is thought to be related to their active cellular uptake by the human renal organic anion transporter-1 (hOAT-1) which is expressed on the cells of the proximal tubule [16]. Although TDF is similar to other nucleotide analogues in its affinity for hOAT-1, in vitro data suggest that TDF is substantially less toxic to renal proximal tubule epithelial cells than cidofovir [16,17]. Also, no significant changes in mitochondrial DNA levels were observed in renal proximal tubule epithelial cells exposed to TDF concentrations ranging from 3 to 300 mM [18].…”

Section: Discussionmentioning

confidence: 99%

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

et al. 2005

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ObjectivesDespite the recent publication of case reports describing various manifestations of tenofovir-related nephrotoxicity, data regarding the incidence of and risk factors for this adverse effect are currently lacking. MethodsA retrospective cohort study of patients from four centres in Toronto, Canada, enrolled in the tenofovir expanded access programme with a minimum of 3 months follow up, was carried out. ResultsA total of 172 patients receiving tenofovir disoproxil fumarate (TDF) for a median of 16 months (range 3-25 months) were included in the study. Seven (4%) patients developed grade 1 (444 mmol/ L from baseline) increases in serum creatinine (SCr) during follow up; no patient developed grade 2 or higher nephrotoxicity. Fifteen (8.7%) patients had an increase in SCr of greater than 1.5 times baseline values during follow up. Four (2.3%) patients discontinued TDF because of an increase in SCr and/or abnormal urinalysis. Of 62 patients with a urinalysis, grade 1 or higher proteinuria (o 3 g/L) was observed in 27 (43%) patients. Only baseline SCr [odds ratio (OR) 5 0.51 per 10 mmol/L increase; P 5 0.0005] and baseline creatinine clearance (1.26 per 10 mL/min increase; P 5 0.01) were significantly associated with ever having a 1.5-fold increase in serum creatinine. Twenty-eight (16%) and 11 (6%) patients developed grade 1 (serum phosphorus 0.71 mmol/L) and grade 2 (serum phosphorus 0.61 mmol/L) hypophosphataemia during follow-up, respectively. ConclusionsAlthough slight increases in SCr did occur after starting TDF, clinically significant nephrotoxicity was rare. The clinical significance of TDF-related hypophosphataemia and proteinuria requires further study.Keywords: adverse effects, anti-HIV agents, creatinine, kidney, tenofovir IntroductionTenofovir disoproxil fumarate (TDF) is the only nucleotide analogue currently available for the management of HIV infection. The efficacy of TDF was initially established in two clinical trials with antiretroviral (ARV)-experienced patients, in which the addition of TDF to stable background therapy resulted in a significant decrease in viral load relative to placebo, with a similar incidence of adverse effects [1]. In addition, study GS-903 established TDF as a comparable alternative to stavudine when used in combination with lamivudine and efavirenz in ARV-naive patients, while eliciting less mitochondrial and metabolic toxicity [2]. The convenience of once-daily administration coupled with a favourable toxicity profile has rendered TDF a welcome addition to the ARV arsenal. Importantly, unlike structurally related nucleotide analogues such as cidofovir and adefovir, clinically significant nephrotoxicity did not emerge as a treatment-limiting adverse effect of TDF in the clinical trials. Furthermore, the renal safety profile of TDF was similar to that of stavudine over 144 weeks of followup in study However, post-marketing experience with TDF has raised the possibility that nephrotoxicity may be an uncommon but important adverse effect of this agent. Several c...

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“…OAT1-mediated uptake of cidofovir leads to selective accumulation and toxicity in renal proximal tubular cells. 111 Similar pharmacokinetics may be used specifically to deliver antiapoptotic drugs to this segment of the nephron. Small molecules may be bound to carriers that lead to specific proximal tubular uptake and organ protection.…”

Section: New Opportunities For Interventionmentioning

confidence: 99%