Hypophosphatemic Osteomalacia Due to Drug-induced Fanconi's Syndrome Associated with Adefovir Dipivoxil Treatment for Hepatitis B

Eguchi, Hironobu; Tsuruta, Munehisa; Tani, Junichi; Kuwahara, Reiichiro; Hiromatsu, Yuji

doi:10.2169/internalmedicine.53.1213

Cited by 26 publications

(23 citation statements)

References 27 publications

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“…ADV also shows no cross-resistance with other nucleoside analogs such as lamivudine (LAM), telbivudine, and entecavir (ETV), and thus is widely used as a rescue therapy for these drugs [7,8] . However, renal dysfunction associated with prolonged use of ADV has been reported recently [9][10][11] . For example, in a study of 10 mg ADV combined with 100 mg LAM, serum creatinine increased in 38% of patients following median treatment duration of 38 mo [12] .…”

Section: Introductionmentioning

confidence: 99%

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

Jia

Ding

Chen

et al. 2015

WJG

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AIM:To evaluate urine β2-microglobulin (β2-M), retinolbinding protein (RBP) excretion, and renal impairment with adefovir dipivoxil (ADV) for chronic hepatitis B. METHODS:We enrolled 165 patients with chronic hepatitis B infection who were treated with ADV monotherapy (n = 90) or ADV plus lamivudine combination therapy (n = 75). An additional 165 chronic hepatitis B patients treated with entecavir were recruited as controls. We detected serum creatinine, urine β2-M, and RBP levels, and estimated the glomerular filtration rate (eGFR) at the initiation of antiviral therapy and every 6 mo for a period of five years. RESULTS:Urine β2-M abnormalities were observed in patients during the first (n = 3), second (n = 7), third (n = 11), fourth (n = 16), and fifth (n = 21) year of ADV treatment. Urinary RBP abnormalities were observed in patients during the first (n = 2), second (n = 8), third (n = 12), fourth (n = 15), and fifth (n = 22) year of ADV treatment. eGFR decreased 20%-30% from baseline in 20 patients, 30%-50% in 12 patients, and > 50% in 3 patients during the five years of treatment. Further analysis indicated that decreases in eGFR of ≥ 30% relative to the baseline level correlated significantly with urine RBP and β2-M abnormalities. In contrast, both serum creatinine and eGFR remained stable in patients treated with entecavir, and only one of these patients developed a urine β2-M abnormality, and two developed urine RBP abnormalities during the five years of treatment. CONCLUSION:Urine RBP and β2-M are biomarkers of renal injury during long-term ADV treatment for chronic hepatitis B, and indicate when treatment should be switched to entecavir.

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Section: Introductionmentioning

confidence: 99%

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

Jia

Ding

Chen

et al. 2015

WJG

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“…Notably, the patient already had osteomalacia associated with Fanconi's syndrome, although she showed only moderate hypophosphatemia and slightly elevated serum levels of ALP and creatinine, which were not necessarily easy to attend to. In fact, ADV-induced osteomalacia is reported to be typically diagnosed by the incidence of bone fractures (8,9); thus the present case is extremely rare in the sense that osteomalacia was found without any sign of bone fractures.…”

Section: Discussionmentioning

confidence: 64%

“…She exhibited no sign of bone anterior posterior fractures when she was referred to our hospital, whereas in the majority of previous reports, an episode of bone fracture afforded the first clue for elucidating the adverse effects of ADV therapy (8). Notably, the patient already had osteomalacia associated with Fanconi's syndrome, although she showed only moderate hypophosphatemia and slightly elevated serum levels of ALP and creatinine, which were not necessarily easy to attend to.…”

Section: Discussionmentioning

confidence: 83%

“…A daily administration of ADV at 10 mg is referred to as ADV therapy for hepatitis B virus (HBV) infection and was considered to be non-nephrotoxic in randomized control trials and cohort studies in Western countries (4)(5)(6). However, reports from East Asia clearly indicate that prolonged ADV therapy induces renal injury (7)(8)(9). Therefore, a sensitive and simple marker is required for long-term ADV administration to predict the early stage of renal injury and prevent serious complications, such as osteomalacia and bone fractures.…”

Section: Introductionmentioning

confidence: 99%

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Urinary β-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection

et al. 2016

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Adefovir dipivoxil (ADV) is effective for hepatitis B virus (HBV) infection; however, ADV may provoke renal injury resulting in osteomalacia, and this side effect is seldom recognized until bone fractures emerge. We herein present a 66-year-old woman with HBV infection who received ADV for 6 years. Although she exhibited no sign of bone fractures, her urinary β-2 microglobulin (β2MG) level increased to 83,837 μg/L and scintigraphy revealed minimal fractures of the third rib. ADV was subsequently reduced and her urinary β2MG rapidly fell to 3,637 μg/L. Conversely, her urinary N-acetyl-β-D-glucosaminidase, and serum phosphate, alkaline phosphatase levels did not respond.

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“…From a point of view of clinical relevance, osteomalacia, which is manifested as bone pain and may contribute to fractures, is regarded as an important side-effect of adefovir therapy. [31][32][33] 29) In conclusion, the present study indicates that 1,25(OH) 2 D 3 treatment can enhance the oral absorption of adefovir dipivoxil (i.e., increased AUC of adefovir, a Mrp4 substrate) via the induction of basolateral Mrp4 function in rat intestine. However, the impact of 1,25(OH) 2 D 3 treatment on the pharmacokinetics of intravenous adefovir is quite limited.…”

Section: Discussionmentioning

confidence: 80%

Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

Yoon

Son

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), an active form of vitamin D, on the oral absorption and disposition of adefovir dipivoxil (P-glycoprotein (P-gp) substrate) and its major active metabolite, adefovir (multidrug resistance-associated protein 4 (Mrp4) substrate), in rats. The pharmacokinetics of intravenous adefovir and oral adefovir dipivoxil was evaluated in control and 1,25(OH) 2 D 3 -treated rats. The intestinal absorption of adefovir dipivoxil was investigated through an in situ closed loop study, and the tissue distribution of adefovir after oral administration of adefovir dipivoxil was evaluated in the two groups. There was no significant difference in pharmacokinetic parameters of intravenous adefovir between the two groups. Importantly, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), peak plasma concentration (C max ) and extent of absolute oral bioavailability (F) of adefovir after oral administration of adefovir dipivoxil were significantly higher in 1,25(OH) 2 D 3 -treated rats than in control rats. In the in situ closed loop study, there was no significant difference in the remaining fraction of adefovir dipivoxil in the duodenum, jejunum and ileum loops between the two groups. In the tissue distribution study after oral administration of adefovir dipivoxil, the tissue-toplasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in 4) During the past decades, significant physiological roles of VDR in calcium and bone homeostasis have been well established. 5)However, it is increasingly recognized that VDR is also crucial in the regulation of drug transporters, and 1,25(OH) 2 D 3 can lead to VDR-mediated changes in target genes of drug transporters. [6][7][8][9][10] Since VDR is abundantly expressed in the intestine, 11) the effects of 1,25(OH) 2 D 3 (i.e., VDR activation) on the expression of intestinal drug transporters are frequently investigated. 1,25(OH) 2 D 3 increases the mRNA expression and function of multidrug resistance protein 1 (MDR1) in the human colorectal adenocarcinoma cell lines, LS174T and Caco-2 cells in vitro. 8,12) It also increases the protein expressions of multidrug resistance-associated protein 2 and 4 (MRP2 and MRP4) in Caco-2 cells. 8,13) In rats, 1,25(OH) 2 D 3 treatment in vivo increases the protein expressions of Mrp2, Mrp3, Mrp4, and the oligopeptide transporter 1 (PepT1) without altering the mRNA and protein expressions of Mdr1a (P-glycoprotein; P-gp). 14)Moreover, our previous studies using rat everted intestinal sac technique confirmed that the in vitro functions of rat intestinal Mrp2, Mrp4 and PepT1, but not P-gp are induced by 1,25(OH) 2 D 3 treatment via VDR activation. 15) However, changes in the expression and/or in vitro functions of drug transporters do not always correlate with the fates of therapeutic agents in the whole body system. Therefore, further studies are needed on the effects of 1,25(O...

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Hypophosphatemic Osteomalacia Due to Drug-induced Fanconi's Syndrome Associated with Adefovir Dipivoxil Treatment for Hepatitis B

Cited by 26 publications

References 27 publications

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

Urinary β-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection

Effects of 1α,25-Dihydroxyvitamin D<sub>3</sub> on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

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