Tenofovir-induced toxicity in renal proximal tubular epithelial cells

Milián, Lara; Peris, José-Esteban; Gandía, Patricia; Andújar, Isabel; Pallardó, Luís; Górriz, José Luis; Blas‐García, Ana

doi:10.1097/qad.0000000000001572

Cited by 16 publications

(11 citation statements)

References 19 publications

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“…For tenofovir, a comparable timedependent effect on cellular metabolic capacity and cytotoxicity was detected. The slightly stronger metabolic response compared to uorescence-based cell death con rms previous observations that tenofovir primarily targets mitochondria (e.g., ultrastructural defects and mtDNA depletion) of the renal proximal tubule [35][36][37][38] . The consequent disruption of mitochondrial biogenesis would explain reduced abundance of mitochondrial enzymes, including dehydrogenases.…”

Section: Discussionsupporting

confidence: 82%

Dissecting drug-induced in vitro cytotoxicity and metabolic dysfunction in conditionally immortalized human proximal tubule cells

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et al. 2021

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Acute kidney injury accounts for 20% of all hospitalized adults, and 14 to 26% is drug-induced, emphasizing the importance of proper nephrotoxicity assessment. The ‘gold standard’ MTT assay is widely used to measure cell viability, but depends on cellular metabolic activity. Consequently, MTT may not be most optimal to assess cytotoxicity, as nephrotoxicity often involves mitochondrial dysfunction. We compared MTT with a direct cell death assay based on a compromised plasma membrane permeability. Mature conditionally immortalized proximal tubule epithelial cells were dose- (0.1-1,000 µM) and time- (0.5, 1, 2, 4, 8 and 24 hours) dependently exposed to a selection of prototypic nephrotoxicants. Dose-dependent reductions in cellular metabolic activity were stronger compared to declines in fluorescence-based cell death, most prominently for cisplatin (1.6 ± 2.0% and 68 ± 4% (mean ± SEM), respectively) and chloroacetaldehyde (2.13 ± 0.05% and 61.0 ± 0.8%). Similar, but more pronounced time-dependent effects were observed, particularly for sanguinarine. We show that assessing cellular metabolic activity by MTT provides a composite readout of cellular metabolic activity and cell death. A nuclear staining approach is preferable when assessing nephrotoxicity of metabolically active compounds. We recommend both assays during drug development to discriminate between metabolically active versus non-active compounds.

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Section: Discussionsupporting

confidence: 82%

Dissecting drug-induced in vitro cytotoxicity and metabolic dysfunction in conditionally immortalized human proximal tubule cells

Hoogstraten

Smeitink

Rüssel

et al. 2021

Preprint

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“…The precise mechanisms of TDF-associated nephrotoxicity are complex; it is associated with acute tubular necrosis of proximal renal tubular cells and with abnormally enlarged mitochondrial within these cells [111]. In experimental models, tenofovir has been shown to accumulate within tubular cells and induce mitochondrial toxicity [112]. Genetic polymorphisms in proximal renal tubular transporters may account for individual susceptibility to these effects [113].…”

Section: Tenofovir Disoproxil Fumaratementioning

confidence: 99%

Contemporary issues and new challenges in chronic kidney disease amongst people living with HIV

2020

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Chronic kidney disease (CKD) is a comorbidity of major clinical significance amongst people living with HIV (PLWHIV) and is associated with significant morbidity and mortality. The prevalence of CKD is rising, despite the widespread use of antiretroviral therapy (ART) and is increasingly related to prevalent non-infectious comorbidities (NICMs) and antiretroviral toxicity. There are great disparities evident, with the highest prevalence of CKD among PLWHIV seen in the African continent. The aetiology of kidney disease amongst PLWHIV includes HIV-related diseases, such as classic HIV-associated nephropathy or immune complex disease, CKD related to NICMs and CKD from antiretroviral toxicity. CKD, once established, is often relentlessly progressive and can lead to end-stage renal disease (ESRD). Identifying patients with risk factors for CKD, and appropriate screening for the early detection of CKD are vital to improve patient outcomes. Adherence to screening guidelines is variable, and often poor. The progression of CKD may be slowed with certain clinical interventions; however, data derived from studies involving PLWHIV with CKD are sparse and this represent an important area for future research. The control of blood pressure using angiotensin converting enzyme inhibitors and angiotensin receptor blockers, in particular, in the setting of proteinuria, likely slows the progression of CKD among PLWHIV. The cohort of PLWHIV is facing new challenges in regards to polypharmacy, drug–drug interactions and adverse drug reactions. The potential nephrotoxicity of ART is important, particularly as cumulative ART exposure increases as the cohort of PLWHIV ages. The number of PLWHIV with ESRD is increasing. PLWHIV should not be denied access to renal replacement therapy, either dialysis or kidney transplantation, based on their HIV status. Kidney transplantation amongst PLWHIV is successful and associated with an improved prognosis compared to remaining on dialysis. As the cohort of PLWHIV ages, comorbidity increases and CKD becomes more prevalent; models of care need to evolve to meet the new and changing chronic healthcare needs of these patients.

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“…Tenofovir disoproxil fumarate (TDF), the prodrug of the nucleotide analogue reverse transcriptase inhibitor (NRTI) tenofovir, is active against both HIV and HBV. TDF use as part of antiretroviral therapy (ART) carries a risk of proximal tubular dysfunction and declining glomerular filtration rate (GFR), [1][2][3] and monitoring of renal function is recommended during treatment. 4,5 The risk is related to both level and length of TDF exposure and is enhanced by co-administration of pharmacological boosters (e.g., ritonavir), low body weight, and pre-existing chronic kidney disease (CKD).…”

Section: Introductionmentioning

confidence: 99%

Renal health after long-term exposure to tenofovir disoproxil fumarate (TDF) in HIV/HBV positive adults in Ghana

Villa

Phillips

Smith

et al. 2018

Journal of Infection

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Tenofovir-induced toxicity in renal proximal tubular epithelial cells

Cited by 16 publications

References 19 publications

Dissecting drug-induced in vitro cytotoxicity and metabolic dysfunction in conditionally immortalized human proximal tubule cells

Dissecting drug-induced in vitro cytotoxicity and metabolic dysfunction in conditionally immortalized human proximal tubule cells

Contemporary issues and new challenges in chronic kidney disease amongst people living with HIV

Renal health after long-term exposure to tenofovir disoproxil fumarate (TDF) in HIV/HBV positive adults in Ghana

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