Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention

Jafari, Alireza; Khalili, Hossein; Dashti‐Khavidaki, Simin

doi:10.1007/s00228-014-1712-z

Cited by 81 publications

(72 citation statements)

References 109 publications

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“…The incidences of tubular dysfunction were demonstrated in 17 to 22% of the tenofovir-treated patients (1,4). The risk factors for nephrotoxicity included long-term use, preexisting kidney diseases, increased age, lower CD4 ϩ cell count, baseline elevation of serum creatinine, dose, concomitant nephrotoxic medications, and low body mass (1,2,4,5). Mitochondria of the proximal tubular cells are the major target of tenofovir toxicity due to their complement of cell membrane transporters that favor tenofovir accumulation, but the exact mechanism of toxicity remains unclear (1,4,5).…”

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confidence: 99%

“…The risk factors for nephrotoxicity included long-term use, preexisting kidney diseases, increased age, lower CD4 ϩ cell count, baseline elevation of serum creatinine, dose, concomitant nephrotoxic medications, and low body mass (1,2,4,5). Mitochondria of the proximal tubular cells are the major target of tenofovir toxicity due to their complement of cell membrane transporters that favor tenofovir accumulation, but the exact mechanism of toxicity remains unclear (1,4,5). Tenofovir undergoes elimination unchanged in urine via the combination of glomerular filtration and active proximal tubular secretion (1,2).…”

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confidence: 99%

“…Approximately 20 to 30% of tenofovir is actively transported into renal proximal tubular cells by the organic anion transporters at the basolateral membrane human OAT1 (hOAT1) and, to a lesser extent, hOAT3 (1,4). Subsequently, the drug is secreted by the ATP-binding cassette subfamily C member 4 (ABCC4; multidrug resistance protein 4 [MRP4]) and ABCC10 (MRP7) (1,4,5) (Fig. 2).…”

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Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11

Tun-Yhong

Chinpaisal

Pamonsinlapatham

et al. 2017

Antimicrob Agents Chemother

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Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, after conversion to tenofovir (TFV), is mainly eliminated by glomerular filtration and active tubular secretion. The major adverse effect of tenofovir is nephrotoxicity; however, the exact mechanism remains poorly understood. In this study, the ATP-binding cassette subfamily C member 11 (ABCC11; multidrug resistance protein 8 [MRP8]) transporter, which is abundant in proximal tubular cells, was demonstrated to act as an efflux transporter of tenofovir. Real-time PCR (RT-PCR) and indirect immunofluorescence assays were used to determine MRP8 overexpression in a continuous cell line. Tenofovir accumulations were assessed by cytotoxicity, cellular transport, and vesicular uptake assays. Substrate specificity was confirmed using MK-571, an MRP-specific inhibitor, and methotrexate, which served as a known substrate. Intracellular and intravesicular concentrations of tenofovir were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 50% cytotoxic concentration (CC 50 ) of TDF in MRP8-overexpressing cells was 4.78 times higher than that of parental cells. Transport assays also showed that the intracellular accumulation of tenofovir in MRP8-overexpressing cells was 55 times lower than that in parental cells and was partly reversed by MK-571. Similarly, an "inside-out" vesicular uptake assay, using Sf9 inverted membrane vesicles to allow measuring of accumulation of the substrates into the vesicles, demonstrated a higher intravesicular concentration of tenofovir in MRP8-overexpressing vesicles than in Sf9 insect control vesicles. These effects were effectively reversed by increasing concentrations of the specific inhibitor MK-571. In conclusion, tenofovir is a new substrate of the MRP8 transporter. An alteration in the activity of this efflux pump may increase the intracellular accumulation of tenofovir in proximal renal tubular cells.

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Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11

Tun-Yhong

Chinpaisal

Pamonsinlapatham

et al. 2017

Antimicrob Agents Chemother

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“…La sindrome di Fanconi è un raro evento avverso correlato a TDF per la quale sono stati identificati alcuni fattori di rischio: elevata creatininemia pre-trattamento, concomitante utilizzo di farmaci nefrotossici, età avanzata, basso valore di linfociti T CD4+ (13). Ad oggi l'esperienza clinica relativa all'utilizzo di TAF nei pazienti in esiti di sindrome di Fanconi è estremamente limitata.…”

Section: Discussioneunclassified

Sindrome di Fanconi Tenofovir-correlata in paziente con coinfezione HIV/HBV: un problema di gestione clinica

Tebini¹,

Zeroli²,

Pizzi³

et al. 2017

JHA

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RiassuntoLa sindrome di Fanconi è un raro evento avverso di tenofovir disoproxil fumarato (TDF). L'osteonecrosi è una condizione multifattoriale descritta nei pazienti HIV-positivi, il cui meccanismo eziologico è dibattuto. Riportiamo il primo caso di un paziente coinfetto HIV-1/HBV trattato con successo con elvitegravir/cobicistat/emtricitabina/tenofovir alafenamide dopo una sindrome di Fanconi TDF-correlata, con miglioramento della funzionalità renale e completa regressione di una precoce osteonecrosi della testa del femore, con un follow-up di 1 anno. Abstract Introduzione L'utilizzo di tenofovir (TVF) è tutt'oggi fondamentale nella terapia antiretrovirale; nei pazienti coinfetti HIV/ HBV costituisce molto spesso una scelta obbligata (1). Tenofovir Alafenamide (TAF) è un nuovo profarmaco di TFV che, rispetto a tenofovir-disoproxil-fumarato (TDF) consente di ottenere adeguate concentrazioni intracellulari del metabolita attivo tenofovir-difosfato (TFV-DP) a fronte di concentrazioni plasmatiche significativamente ridotte (2-3). Anche a livello epatico, TAF consente il raggiungimento di concentrazioni più elevate di TFV-DP, con una emivita superiore alle 24 ore (4). Tenofovir alafenamide ha un minore impatto sulla funzionalità renale e sul metabolismo osseo rispetto a TDF, grazie alle minori concentrazioni plasmatiche di TFV, come ampiamente dimostrato da studi clinici relativi alla co-formulazione di TAF 10 mg con elvitegravir 150 mg, cobicistat 150 mg, emtricitabina 200 mg (E/C/F/TAF) (5-6). L'esposizione prolungata ad alti livelli plasmatici di TFV è associata a disfunzione tubulare e circa lo 0,3% dei pazienti in terapia con TDF può sviluppare una sindrome di Fanconi (7), una condizioni rara caratterizzata da una disfunzione del tubulo renale prossimale che altera il trasporto di aminoacidi, glucosio, fosfato, acido urico, sodio, potassio, bicarbonato e proteine (8). L'utilizzo di TDF è notoriamente correlato anche a riduzione della densità minerale ossea nell'anca e nella colonna, tramite un aumentato turnover osseo, correlato anche alla perdita di fosfati dovuta alla tossicità tubulare (9-12). Descriviamo di seguito il caso di un paziente coinfetto HIV-1/HBV in esiti di sindrome di Fanconi TDF-correlata e affetto da un'iniziale osteonecrosi della testa del femore sinistro, trattato con E/C/F/TAF con miglioramento della funzionalità renale e completa regressione dell'osteonecrosi femorale, con un anno di follow-up. Case report

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“…Since nucleotide analogs, such as adefovir dipivoxil, are excreted by the kidney in their original form, combined antiviral drug treatment tends to increase the burden of the kidney (47,48). Further studies are required to investigate whether combined antiviral drug treatment increases the risk of renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Adefovir dipivoxil-induced Fanconi syndrome and its predictive factors: A study of 28 cases

et al. 2016

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Abstract. The aim of the present study was to identify monitoring and prevention measures as well as predictive factors for early detection of renal toxicity associated with long-term administration of adefovir dipivoxil in order to avoid progression to Fanconi syndrome. Clinical data of 28 patients with Fanconi syndrome caused by long-term administration of adefovir dipivoxil for the treatment of chronic hepatitis B virus (HBV) infection were collected pre-and post-administration for analysis. Patients presented with fatigue, progressive systemic pain in multiple bones and joints, as well as difficulty in walking and pathological fractures in a number of severe cases. Laboratory examinations revealed hypophosphatemia, elevated serum cystatin C (Cys-C), elevated serum creatinine (SCr), reduced glomerular filtration rate (GFR), positive urinary protein, erythrocytes and glucose, as well as osteoporosis. In consequence, adefovir dipivoxil administration was stopped, and patients received concentrated divitamins, sodium phosphate syrup and calcitriol. Symptoms and abnormalities in laboratory examinations were significantly improved in all patients after 2-6 months. Therefore, serum phosphate, SCr, routine urine parameters, Cys-C and GFR should be monitored regularly in chronic HBV patients treated with adefovir dipivoxil. The following factors were identified as predictive of kidney damage and Fanconi syndrome: Age ≥40 years, living in rural areas, previous renal toxicity, estimated GFR (eGFR) <90 ml/min/1.73 m 2 , hypertension, diabetes, cirrhosis and duration of adefovir dipivoxil treatment exceeding 24 months. The present results indicate that timely termination of adefovir dipivoxil treatment and replacement with other antiviral agents is critical once renal impairment appears, and that it is necessary to change to other antiviral agents and prolong the interval of administration according to the eGFR level.

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Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention

Cited by 81 publications

References 109 publications

Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11

Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11

Sindrome di Fanconi Tenofovir-correlata in paziente con coinfezione HIV/HBV: un problema di gestione clinica

Adefovir dipivoxil-induced Fanconi syndrome and its predictive factors: A study of 28 cases

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