• drugs for the heart
• glomerulopathies
• nephrotoxicity

• Adefovir dipivoxil
• Fanconi syndrome
• Femoral neck fracture
• Osteomalacia
• Periprosthetic fractures

• Humans
• Osteomalacia/chemically induced
• Follow-Up Studies
• Periprosthetic Fractures
• Treatment Outcome

• Mitochondrial dysfunction
• Myotoxicity
• Oxidative stress
• Telbivudine

• Mice
• Animals
• Mice, Inbred C57BL
• Telbivudine
• Muscular Diseases/chemically induced
• DNA, Mitochondrial
• Mitochondria

• Allografts
• Antiviral Agents/adverse effects
• Creatinine
• Fanconi Anemia/pathology
• Fanconi Syndrome/chemically induced
• Fanconi Syndrome/diagnosis
• Fanconi Syndrome/therapy
• Humans
• Kidney Transplantation/adverse effects
• Kidney Tubules, Proximal/pathology
• Renal Insufficiency
• Retrospective Studies
• Scoliosis/chemically induced
• Scoliosis/pathology
• Tacrolimus/adverse effects

In line with recent OECD activities on the use of AOPs in developing Integrated Approaches to Testing and Assessment (IATAs), it is expected that systematic mapping of AOPs leading to systemic toxicity may provide a mechanistic framework for the development and implementation of mechanism-based in vitro endpoints. These may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies. Focusing on kidney and in particular the proximal tubule epithelium as a key target site of chemical-induced injury, the overall aim of this work is to contribute to building a network of AOPs leading to nephrotoxicity. Current mechanistic understanding of kidney injury initiated by 1) inhibition of mitochondrial DNA polymerase γ (mtDNA Polγ), 2) receptor mediated endocytosis and lysosomal overload, and 3) covalent protein binding, which all present fairly well established, common mechanisms by which certain chemicals or drugs may cause nephrotoxicity, is presented and systematically captured in a formal description of AOPs in line with the OECD AOP development programme and in accordance with the harmonized terminology provided by the Collaborative Adverse Outcome Pathway Wiki. The relative level of confidence in the established AOPs is assessed based on evolved Bradford-Hill weight of evidence considerations of biological plausibility, essentiality and empirical support (temporal and dose-response concordance).

• Bundesministerium für Bildung und Forschung
• ZonMw

• Chronic kidney disease
• Long-term follow-up
• Real-world study
• Renal function

• Adult
• Antiviral Agents/adverse effects
• Female
• Guanine/analogs & derivatives
• Hepatitis B, Chronic/drug therapy
• Humans
• Kidney/physiology
• Male
• Middle Aged
• Retrospective Studies
• Tenofovir/adverse effects
• Treatment Outcome

More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was introduced for the long-term treatment of hepatitis B virus (HBV) infection. Because the life expectancy of HBV-infected individuals has increased, the adverse effects of long-term treatment with antiviral therapies are increasingly observed, and nephrotoxicity is one of the most severe adverse effects of ADV. Therefore, the number of cases may be far higher than reported. Moreover, ADV-induced FS is often misdiagnosed or diagnosed long after it first develops. ADV-induced FS may seriously decrease patient quality of life and lead to bone fractures and even disability. Although progress has been made in the identification of biomarkers and treatments, few systematic clinical guidelines or clinical reviews for FS induced by ADV have been reported. In this study, we highlighted the recent progress toward understanding of FS induced by ADV, described a clinical case, and summarized the primary characteristics and laboratory findings of this disease.

• Fanconi syndrome
• adefovir dipivoxil
• adverse effects
• antiviral therapy
• hepatitis B virus
• hypophosphatemia
• nephrotoxicity
• osteomalacia

• Antiviral agents
• Guanine
• Hepatitis B, chronic
• Kidney diseases

• adefovir
• adenine
• chronic hepatitis B
• chronic renal insufficiency
• giant mitochondria
• glomerular and tubulointerstitial diseases
• organophosphonates

The aim of the present study was to evaluate the effects of switching to tenofovir alafenamide (TAF) in patients who had received a nucleos(t)ide analog (NA) for the treatment of chronic hepatitis B (CHB). The data from 33 Japanese patients with CHB who received TAF therapy after using NA [adefovir dipivoxil (ADV) and/or tenofovir disoproxil fumarate (TDF)] were retrospectively analyzed. Specifically, the biochemical and virological markers from the start of the TAF treatment to 6 months later were assessed. Comparative evaluation was performed by dividing patients into two groups: Long-term (n=19) and short-term administration groups (n=14), with a cutoff administration duration of 10 years. In all 33 patients, the levels of serum hepatitis B surface antigen (HBsAg; 1,126±1,724 to 1,001±1,591 IU/ml; P<0.0001), serum alkaline phosphatase (ALP) (320±126 to 283±124 U/l; P=0.028), serum bone specific alkaline phosphatase (19.7±9.0 to 17.7±8.0 µg/l; P=0.0006) and urine β2-microglobulin-creatinine ratio (U-BMG/Cr; 5,224±17,471 to 3,547±14,652 µg/g·Cre; P=0.002) significantly decreased from baseline after 6 months. Serum HBsAg, serum ALP and U-BMG/Cr showed a significant reduction in both groups. In conclusion, switching from ADV or TDF to TAF resulted in a decrease in serum HBsAg and improvement in serum ALP and U-BMG/Cr after 6 months of treatment in patients regardless of history of treatment with NA.

• adefovir dipivoxil
• hepatitis B virus
• tenofovir alafenamide
• tenofovir disoproxil fumarate

The kidneys utilize roughly 10% of the body’s oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria, having the second highest mitochondrial content and thus oxygen consumption of our body. The bulk of the ATP generated in the kidneys is consumed to move solutes toward (reabsorption) or from (secretion) the peritubular capillaries through the concerted action of an array of ATP-binding cassette (ABC) pumps and transporters. ABC pumps function upon direct ATP hydrolysis. Transporters are driven by the ion electrochemical gradients and the membrane potential generated by the asymmetric transport of ions across the plasma membrane mediated by the ATPase pumps. Some of these transporters, namely the polyspecific organic anion transporters (OATs), the organic anion transporting polypeptides (OATPs), and the organic cation transporters (OCTs) are highly expressed on the proximal tubular cell membranes and happen to also transport drugs whose levels in the proximal tubular cells can rapidly rise, thereby damaging the mitochondria and resulting in cell death and kidney injury. Drug-induced kidney injury (DIKI) is a growing public health concern and a major cause of drug attrition in drug development and post-marketing approval. As part of the article collection “Mitochondria in Renal Health and Disease,” here, we provide a critical overview of the main molecular mechanisms underlying the mitochondrial damage caused by drugs inducing nephrotoxicity.

• antibiotic
• anticancer
• antiviral
• drug-induced kidney injury
• mitochondria
• oxidative stress
• proximal tubular cells

• Fanconi's syndrome
• adefovir dipivoxil
• chronic hepatitis B
• hypophosphataemic osteomalacia

• Adefovir
• Anti-HBV drugs
• Drug resistance
• Entecavir
• HBV
• Nucleoside/nucleotide reverse transcriptase inhibitors

• Adenine/analogs & derivatives
• Adenine/pharmacology
• Animals
• Antiviral Agents/chemical synthesis
• Antiviral Agents/pharmacology
• Drug Resistance, Viral
• Guanine/analogs & derivatives
• Guanine/pharmacology
• Hep G2 Cells
• Hepatitis B virus/classification
• Hepatitis B virus/drug effects
• Hepatitis B, Chronic/drug therapy
• Humans
• Mice
• Mice, Transgenic
• Models, Molecular
• Nucleosides/chemical synthesis
• Nucleosides/pharmacology
• Organophosphonates/pharmacology
• Viral Load

• R01 AI121315 NIAID NIH HHS
• ZIA BC011486 Intramural NIH HHS

• HBs-antigen
• entecavir
• medication compliance
• tenofovir alafenamide fumarate

• Antiviral
• HBV
• Nephrotoxicity
• Nucleoside analogues
• Tenofovir

• ATP
• Bioenergetics
• Defect
• Energy crisis
• Nephrotoxicity
• Oxidative stress
• Reabsorption

Adefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D₃.

A 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, ^99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient’s adefovir dipivoxil dose and added calcitriol (active vitamin D₃), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D₃ supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers.

Although denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.

• Adefovir dipivoxil
• Chronic hepatitis B
• Denosumab
• Fanconi syndrome
• Osteomalacia
• Osteoporosis

• Fanconi's syndrome
• adefovir dipivoxil
• hepatitis B virus
• hypophosphatemia
• osteomalacia

• Fanconi syndrome
• adefovir
• diabetic kidney disease
• osteomalacia
• vitamin D deficiency

• Adenine/adverse effects
• Adenine/analogs & derivatives
• Adenine/therapeutic use
• Aged
• Antiviral Agents/adverse effects
• Antiviral Agents/therapeutic use
• Diabetes Mellitus, Type 2/complications
• Diabetic Nephropathies/diagnosis
• Diagnostic Errors
• Fanconi Syndrome/chemically induced
• Fanconi Syndrome/complications
• Fanconi Syndrome/diagnosis
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/drug therapy
• Humans
• Hypophosphatemia/diagnosis
• Hypophosphatemia/etiology
• Male
• Organophosphonates/adverse effects
• Organophosphonates/therapeutic use
• Osteomalacia/diagnosis
• Osteomalacia/etiology
• Vitamin D Deficiency/diagnosis

• anti-hepatitis B drugs
• common deletion
• mitochondrial DNA
• mitochondrial myopathy
• oxidative damage

• Antiviral drugs
• acute kidney injury (AKI)
• acyclovir
• adefovir
• atazanavir
• cidofovir
• foscarnet
• indinavir
• tenofovir.

• Acute Kidney Injury/chemically induced
• Antiviral Agents/adverse effects
• Apoptosis/drug effects
• Humans
• Kidney Tubular Necrosis, Acute/chemically induced
• Mitochondria/drug effects
• Nephritis, Interstitial/chemically induced

• 6-HD, 6-hydroxydopamine
• AIDS, acquired immune deficiency syndrome
• ALB, albumin
• ANOVA, analysis of variance
• AREC, animal research ethics committee
• BGL, blood glucose levels
• BRU, Biomedical Resource Unit
• BUN, blood urea nitrogen
• BW, body weight
• CAT, catalase
• DETAPAC, diethylenetriamine – penta acetic acid
• DNA, deoxyribonucleic acid
• DTNB, 5, 5'-dithiobis-(2-nitrobenzoic acid)
• GSH, reduced glutathione
• H and E, haematoxylin and eosin
• HAART
• HAART, highly active antiretroviral therapy
• HIV, human immunodeficiency virus
• Histopathology
• KW, kidney weight
• KWBR, kidney weight body ratio
• Kidney
• LPO, lipid peroxidation
• M. charantia, Momordica charantia
• MDA, malondialdehyde
• MT, Masson’s Trichome
• Momordica charantia
• NRTIs, nucleoside reverse transcriptase inhibitors
• Nephrotoxicity
• PAS, Periodic Acid Schiff
• PBS, phosphate buffer solution
• PLWHA, people living with HIV and AIDS
• ROS, reactive oxygen species
• SCr, serum creatinine
• SD, standard deviation
• SDS, sodium dodecyl sulfate
• SOD, superoxide dismutase
• Sprague-Dawley rats
• TBARS, thiobarbituric acid reactive substances
• TCA, trichloroacetic acid
• UKZN, University of KwaZulu Natal
• rpm, revolutions per minute

The long-term use of adefovir and tenofovir–antiviral medications commonly used to treat chronic hepatitis B–can be associated with proximal renal tubular dysfunction resulting in significant hypophosphatemic osteomalacia. However, there have been few reports about pathological fractures requiring surgical stabilization in cases of antiviral drug-induced hypophosphatemic osteomalacia. We present the case of a 51-year-old man who sustained bilateral pathological hip fractures associated with antiviral drug-induced hypophosphatemic osteomalacia. To treat a lamivudine-resistant hepatitis-B viral infection, the patient received adefovir for 7 years followed by tenofovir for the subsequent 3 years. He had suffered from polyarthralgia and generalized weakness for 2 years prior to presentation at our clinic. Misdiagnosis and inadequate management of his condition accelerated weakness of the bone matrix and ultimately induced pathological fractures. The patient was managed via cementless total hip arthroplasty on the left hip and internal fixation on the right hip. This case highlights that orthopaedic surgeons should consider the possibility of hypophosphatemic osteomalacia if patients receiving antiviral drugs complain of polyarthralgia and generalized weakness.

• Antiviral agents
• Hypophosphatemic osteomalacia
• Pathological fracture

• Cubilin
• Fanconi syndrome
• Megalin
• Nephrotoxicity
• Tenofovir
• Tubulopathy

To investigate the predictors of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) and to monitor for early detection.

Hospitalized patients who were diagnosed with ADV-related hypo-phosphatemic osteomalacia were recruited and retrospectively analyzed in our hospital from January 2012 to December 2016. A telephone interview was conducted at 1, 3, 6, 9, 12, and 24 months after cessation of ADV.

In the 8 patients enrolled in the study, the hypophosphatemic osteomalacia symptoms developed at an average of 5.14 (4–7) years since ADV treatment (10 mg/d). The average alkaline phosphatase (ALP) level was 279.50 (137–548) U/L, which was significantly higher than the normal level (45–125 U/L). The serum phosphorus level was an average of 0.59 (0.43–0.69) mmol/L, which was lower than the normal range (2.06–2.60 mmol/L). Serum calcium levels of the enrolled patients remained within normal limits. Reduced estimated glomerular filtration rate (eGFR <29 mL/min/1.73 m²) was seen in 4 cases. The clinical manifestations were mainly progressive systemic bone and joint pain, frequent fractures, trouble in walking, height reduction (4–6 cm), and so on. After cessation of ADV, symptoms like bone pain resolved gradually. Serum phosphorus level restored to normal in 4.5 months after the withdrawal of ADV. However, in 4 patients, renal function failed to return to normal in 24 months.

More attention should be paid to the duration of ADV treatment. The level of serum phosphorus and ALP, as well as renal function, should be monitored for early detection of potential adverse drug reactions.

• adefovir dipivoxil
• follow-up
• hypophosphatemic osteomalacia
• long term
• renal tubular dysfunction
• serum phosphate

• adefovir
• eGFR
• hepatitis B
• hypophosphatemia
• osteomalacia
• renal injury

An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy.

The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non–anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient’s symptoms and laboratory findings improved significantly.

The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus.

• Adefovir
• Nephrolithiasis
• Obstructive nephropathy
• Osteomalacia
• Osteoporosis
• Renal Fanconi syndrome

• BCRP
• MATE1
• MATE2-K
• MDR1
• MRP2
• OAT
• OCT2
• OCTN2
• Transporters

• adefovir nephrotoxicity
• atrophy
• chronic allograft nephropathy (CAN)
• chronic kidney disease (CKD)
• cytochrome C oxidase
• end-stage renal disease (ESRD)
• enzyme histochemistry
• functional electron microscopy
• hypertension
• hypertrophy
• lupus erythematosus
• megamitochondria
• transplantation

• Hepatitis B
• Pharmacogenetics
• Pharmacokinetics
• Pradefovir
• Single ascending dose
• Tolerability

Most people develop acute hepatitis B virus (HBV)-related hepatitis that is controlled by both humoral and cellular immune responses following acute infection. However, a number of individuals in HBV-endemic areas fail to resolve the infection and consequently become chronic carriers. While a vaccine is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Standard treatment in HBV infection includes IFN-α, nucleoside, or nucleotide analogs, which has direct antiviral activity and immune modulatory capacities. However, immunological control of the virus is often not durable. A robust T-cell response is associated with control of HBV infection and liver damage; however, HBV-specific T cells are deleted, dysfunctional, or become exhausted in chronic hepatitis patients. As a result, efforts to restore virus-specific T-cell immunity in chronic HBV patients using antiviral therapy, immunomodulatory cytokines, or therapeutic vaccination have had little success. Adoptive cell transfer of T cells with specificity for HBV antigen⁺ cells represents an approach aiming to ultimately eliminate residual hepatocytes carrying HBV covalently closed circular DNA (cccDNA). Here, we discuss recent findings describing HBV immunopathology, model systems, and current therapies.

• hepatitis B virus
• immunopathology
• immunotherapy for HBV
• model systems
• therapies

Controversy remains as to whether antiviral agents contribute to renal dysfunction in patients with chronic hepatitis B virus (HBV) infection. Thus, the aim of study was to analyze the changes in renal function of chronic hepatitis B (CHB) patients in response to anti-HBV therapy and the association with treatments.

We performed a retrospective observational cohort study to investigate factors associated with renal function in 249 Chinese CHB patients who were treated with pegylated interferon α-2a (PEG-IFN-α-2a) or nucleos(t)ide analogues for 48 weeks. Changes of estimated glomerular filtration rate (eGFR), which was computed with both the Chronic Kidney Disease Epidemiology Collaboration and the Modification of Diet in Renal Disease formulas, were tested by repeated measures One-way analysis of variance within groups. A linear mixed effects model for repeated measures was also used to evaluate the association between baseline information and eGFR changes over time in all enrolled patients. The model considered the baseline age, sex, HBV DNA, aminotransferase, blood urea nitrogen, treatment group, time, and group-by-time interaction as fixed effects and incorporated random effects for individual subjects.

The eGFR increased in patients given PEG-IFN-α-2a, decreased in patients given adefovir, but remained stable in patients given entecavir. Age and blood urea nitrogen were significant negative predictive factors for eGFR changes.

In real-life study, PEG-IFN-α-2a therapy in CHB patients increased eGFR, thus may associate with renoprotective effects when compared with adefovir or entecavir therapies.

• Antiviral
• Chronic hepatitis B
• Chronic kidney diseases
• Drug
• Mixed Linear Model

• Humans
• Kidney Diseases/chemically induced
• Kidney Diseases/pathology
• Kidney Tubular Necrosis, Acute/pathology
• Nephritis, Interstitial/pathology
• Toxins, Biological/pharmacology

• adefovir
• entecavir
• hepatitis B
• mitochondrial toxicity.
• renal function
• renal toxicity
• telbivudine
• tenofovir

• Acute kidney injury
• Antiretroviral
• Antirétroviral
• Chronic kidney disease
• Drug nephrotoxicity
• Drug side effect
• Effets secondaires médicamenteux
• Fanconi syndrome
• Insuffisance rénale aiguë
• Insuffisance rénale chronique
• Syndrome de Fanconi
• Toxicité rénale
• Tubulopathie
• Tubulopathy

• Adefovir
• Chronic
• Glomerular Filtration Rate
• Hepatitis B
• Telbivudine

• Adenine/adverse effects
• Adenine/analogs & derivatives
• Aged
• Antiviral Agents/therapeutic use
• Female
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/drug therapy
• Humans
• Japan
• Organophosphonates/adverse effects
• Osteomalacia/chemically induced
• Osteomalacia/diagnosis
• Osteomalacia/therapy
• beta 2-Microglobulin/urine

• Bordetella pertussis
• PMEA
• adenylate cyclase toxin
• bisamidates
• nucleosides
• phosphonates
• prodrugs

• Adefovir
• hepatitis B
• lamivudine-resistant
• nephrotoxicity
• renal
• transplant.

• Acute kidney injury
• HIV-associated nephropathy
• Hemolytic uremic syndrome
• Proteinuria
• Renal urinary biomarkers

• Animals
• Biomarkers/urine
• Child, Preschool
• HIV Infections/complications
• HIV Infections/urine
• Humans
• Kidney Diseases/diagnosis
• Kidney Diseases/urine
• Kidney Diseases/virology

• HL55605 NHLBI NIH HHS
• U54HD071601 NICHD NIH HHS
• DK49419 NIDDK NIH HHS
• R01 DK103564 NIDDK NIH HHS
• DK103564 NIDDK NIH HHS
• R01 DK108368 NIDDK NIH HHS
• R01 DK049419 NIDDK NIH HHS
• U54 HD071601 NICHD NIH HHS
• R01 HL055605 NHLBI NIH HHS