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Technetium pertechnetate bone scan showing multifocal osteoblastic lesions involving the bilateral ribs, lumbar spine, hip joints, and ankle joints.
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Adefovir dipivoxil (ADV) is commonly used as an antiviral agent in the treatment of chronic hepatitis B or human immunodeficiency virus infection. Nephrotoxicity has been shown to occur at daily dosages of 60-120 mg. Fanconi's syndrome is a generalized dysfunction of the renal proximal tubular cells, which is usually accompanied by complications. H...
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Context 1
... radiological evaluation included a technetium per- technetate bone scan, which showed increased uptake in the lumbar spine, multiple ribs, both knees, and both an- kle joints (Fig. 2). X-rays of these areas showed lumbar spine spondylosis and multiple rib fractures. Dual-energy X-ray absorptiometry (DXA) showed a decreased lumbar spine bone mineral density (BMD) of 0. Because we excluded other causes, it was thought to be caused by interstitial nephritis secondary to the antiviral medication. So, the patient stopped ...
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Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the a...
Citations
... Moreover, six months after treatment with TDF, 59.5% of patients showed elevated urinary β2-microglobulin (U-BMG), which is a sensitive marker for renal tubular dysfunction [11]. Furthermore, bone metabolism abnormalities and subsequent bone fracture have been reported to develop in patients with the long-term use of ADV/TDF [12][13][14][15]. As the life expectancy of HBV-infected individuals has increased, the long-term adverse effects of antiviral therapies have increasingly emerged [16]. ...
Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement of the natural course of patients with CHB. However, renal dysfunction is becoming an important issue for the management of CHB. Renal dysfunction develops in patients with the long-term treatment of NAs including adefovir dipivoxil and tenofovir disoproxil fumarate. Recently, several studies have reported that the newly approved tenofovir alafenamide (TAF) has a safe profile for the kidney due to greater plasma stability. In this mini-review, we discuss the effectiveness of switching to TAF for NAs-related renal tubular dysfunction in patients with CHB.
... TAF was shown to have less influence on the glomerular filtration rate (GFR) and renal tubule function than TDF in international phase III trials (4-6). Long-term use of ADV and TDF has been reported, and there are several cases where renal and tubular dysfunction and bone metabolism abnormalities occurred (16)(17)(18)(19). At present, few studies have reported the effect of switching to TAF after long-term use of other NAs (particularly the nucleotide group). ...
... Although ADV was changed to TDF in ADV-related Fanconi syndrome, TDF is structurally similar to ADV, and renal dysfunction and Fanconi syndrome due to TDF have also been reported. Therefore, as in ADV treatment, monitoring of renal and tubular functions is also required (17,18,38). ...
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.
... 29,35 Furthermore, according to prior research, 23 the apparent symptoms appear after a median of 30.5 months of ADV treatment. The main characteristics of 32 patients with ADV-induced FS, including eight patients in our institution and 24 published cases, are summarized in Table 4. 5,18,22,23,[36][37][38][39][40][41][42][43] ...
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.
... The true incidence of ADV-induced Fanconi syndrome has not been clarified in any prospective or retrospective studies to date. An increasing number of case reports have described the development of Fanconi syndrome among patients receiving long-term low dose ADV therapy (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). However, awareness of this condition seems unsatisfactory in daily clinical practice, since some patients with ADVinduced Fanconi syndrome have been undiagnosed or even misdiagnosed. ...
A 68-year-old man with type 2 diabetes mellitus and chronic hepatitis B infection was referred to the nephrology department before planned surgery for hepatocellular carcinoma. He had been receiving low-dose adefovir dipivoxil (ADV) for 11 years. Laboratory findings revealed impaired re-absorption in the proximal renal tubules. He had been diagnosed with diabetic kidney disease and osteomalacia due to vitamin D deficiency; thus, ADV was not discontinued until he was referred to us. In this case, concomitant diabetes mellitus and vitamin D deficiency might have prevented the early diagnosis of ADV-induced Fanconi syndrome.
... Adefovir causes dose-related renal toxicity due to renal tubular dysfunction. Although low-dose ADV therapy (10 mg/day) has been reported to be safe (1,2), there is an increasing number of case reports demonstrating hypophosphatemic osteomalacia caused by proximal renal tubular dysfunction, a feature of Fanconi's syndrome (3)(4)(5)(6)(7). However, pathological fractures related to low dose ADV therapy is still uncommon. ...
Adefovir dipivoxil (ADV) is a nucleotide analogue used in the chronic hepatitis B treatment. Proximal renal tubular dysfunction is one of the adverse effects of this agent and characterized with hypophosphatemia and osteomalacia. However, reduced bone mineral density with fracture due to ADV therapy has not been reported before. We aimed to report a 55-year-old male patient with proximal femur fracture who developed hypophosphatemic osteomalacia while using low dose of adefovir (10 mg/day) for chronic hepatitis B treatment for 10 years.
... A slight reversible increase in serum creatinine is reported in fewer than 1% to 3% of patients after 3-5 years of treatment with ADV 10 mg and TDF 300 mg [4][5][6]. Despite the safety profile of 10 mg ADV from large clinical trials [4][5][6], ADV-induced Fanconi's syndrome, proximal renal tubular dysfunction (PRTD), and hypophosphatemia have been reported in CHB patients [7][8][9][10][11][12][13]. PRTD, hypophosphatemia, and Fanconi's syndrome are also common in human immunodeficiency virus-(HIV-) infected patients receiving TDF as a part of highly active antiretroviral therapy [14][15][16]. ...
... Reversibility of renal dysfunction has been shown in HIV-infected patients after cessation of TDF [21][22][23][24][25]. A few cases of reversible TDF or ADV-induced PRTD and Fanconi's syndrome have been reported in CHB patients after stopping treatment with nucleotide analogues [12,26]. We aimed to prospectively assess the clinical and laboratory outcomes of PRTD in CHB patients after discontinuation of TDF or ADV. ...
... The rapid decline of renal losses of urinary protein and 2-microglobulin after cessation of nucleotide analogue signified the restoration of proximal renal tubular structure and function. Previously, there have been a few case reports describing the reversal of ADV and TDF-related Fanconi's syndrome after TDF withdrawal in patients with CHB [12,26]. In contrast, our study showed that nucleotide analogue-related PRTD could be resolved in 16 CHB patients after discontinuation of nucleotide analogue similar to the phenomenon that occurs in HIV-infected patients [21][22][23][24][25]. ...
Aims
Proximal renal tubular dysfunction (PRTD) is an infrequent complication after nucleotide analogue therapy. We evaluated the outcomes of PRTD and nephrotoxicity after nucleotide analogue withdrawal in chronic hepatitis B (CHB).
Methods
A longitudinal follow-up study was performed in patients with PRTD after nucleotide analogue discontinuation. Serum and urine were collected at baseline and every 3 months for one year. The fractional excretion of phosphate (PO4), uric acid (UA), and potassium and tubular maximal reabsorption rate of PO4 to glomerular filtration rate (TmPO4/GFR) were calculated. Renal losses were defined based on the criteria of substance losses. Subclinical PRTD and overt PRTD were diagnosed when 2 and ≥3 criteria were identified.
Results
Eight subclinical and eight overt PRTD patients were enrolled. After nucleotide analogue withdrawal, there were overall improvements in GFR, serum PO4, and UA. Renal loss of PO4, UA, protein, and β2-microglobulin reduced over time. At one year, complete reversal of PRTD was seen in 13 patients (81.2%). Improvements in PRTD were seen in all but one patient.
Conclusion
One year after nucleotide analogue withdrawal, PRTD was resolved in most patients. Changes in TmPO4/GFR, urinary protein, and β2-microglobulin indicate that urinary biomarkers may represent an early sign of PRTD recovery.
... 1,2 Several side effects associated with adefovir are reported, including acute renal failure and Fanconi syndrome (FS). 3,4 FS results from dysfunction of reabsorption in the proximal tubules of the kidney. This impairment causes increased excretion of solutes, such as amino acids, glucose, uric acid, bicarbonate, and phosphate. ...
... 6 Nephrotoxicity associated with high dose of adefovir, 120 mg/day, used in patients with HIV is well known. 1 Adefovir has an adverse event profile similar to that of a placebo when used at a dose of 10 mg/day in patients with chronic hepatitis B infections. 2 However, nephrotoxicity including FS and hypophosphatemic osteomalacia has been described in several reports in patients taking a low dose of 10 mg/day. 3,4 Presently, the patient's symptoms were nonspecific. Symptoms including myalgia, general weakness, or multiple fracture without an explainable cause have been described. ...
... Symptoms including myalgia, general weakness, or multiple fracture without an explainable cause have been described. 3,4 In our opinion, suspicion of FS is most important to make a diagnosis, and urinalysis is the most valuable screening test for FS. FS should be considered in non-diabetic patients when chronic glycosuria is evident and when a tubular range of proteinuria exists or when the levels of phosphorus and uric acid are lower than normal range or in the lower normal margin. ...
Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia.
... Adefovir bisphosphonate, which is the effective metabolite of adefovir dipivoxil, tends to suppress the duplication of mitochondrial DNA, leading to mitochondrial DNA loss in the renal proximal tubule, thus affecting renal tubular reabsorption and secretion (36). Previous studies demonstrated that adefovir dipivoxil-induced proximal tubule damage tends to lead to Fanconi syndrome, which presents different degrees of hypophosphatemia, hypouricemia and combined dysfunction of the proximal renal tubule (41). Patients with adefovir dipivoxil-induced Fanconi syndrome in the present study were characterized by a number of features. ...
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 m², 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.
... In this case study, Fanconi syndrome, which is associated with the use of multiple medications and chemicals [2], was most likely drug-induced. Several drugs, including aminoglycosides, ifosfamide, cisplatin, streptozocin, mercaptopurine, tetracycline, and valproate, have been found to be associated with Fanconi syndrome [2]. ...
... In this case study, Fanconi syndrome, which is associated with the use of multiple medications and chemicals [2], was most likely drug-induced. Several drugs, including aminoglycosides, ifosfamide, cisplatin, streptozocin, mercaptopurine, tetracycline, and valproate, have been found to be associated with Fanconi syndrome [2]. ...
... TDF at 300 mg daily is rarely associated with nephrotoxicity, at least when used for 1-2 years [7]. However, several case reports have described Fanconi syndrome with prolonged, low-dose ADV therapy [2] in HIV or CHB patients treated with TDF [8]. Therefore, ADV and TDF might be associated with rare instances of proximal renal tubular dysfunction, and nephrotoxicity can be affected by the treatment duration and dose. ...
Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogues used to treat chronic hepatitis B (CHB) infection. Nephrotoxicity associated with the use of these medications causes Fanconi syndrome, a rare condition involving generalized dysfunction of the proximal renal tubule causing impaired reabsorption of glucose, uric acid, and phosphate. Fanconi syndrome has been previously reported in patients with human immunodeficiency virus (HIV) or HIV-CHB coinfection treated with other antiretroviral therapies. However, it is rarely reported in patients with CHB monoinfection. We observed a case of Fanconi syndrome in a 61-year-old woman with CHB monoinfection and a history of long-term ADV therapy (42 months), followed by TDF treatment for 9 months. She presented with ankle pain and a tingling sensation in both lower extremities. Laboratory tests revealed hypokalemia, hypocalcemia, hypophosphatemia, hypouricemia, proteinuria, and glycosuria. This case illustrates the importance of recognizing Fanconi syndrome associated with nucleotide analogue treatment and the need to carefully observe symptoms and monitor renal function in these patients.
... Renal toxicity may also be manifested by proximal tubular cell toxicity without a rise in serum creatinine concentration, including a Fanconi-like syndrome characterized by proteinuria, normoglycemic glycosuria and hyperphosphaturia [17,18]. Several cases of this syndrome have been reported in patients taking nucleotide analogs for CHB [19,20]. Differences in the age, body weight, baseline renal function, prevalence of hypertension, diabetes mellitus and cirrhosis in previous clinical trials and cohorts may also account for the differences in renal dysfunction reported after treatment with nucleotide analogs [11,13,19]. ...
Background
There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs.
Methods
We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4–101 months).
Results
Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6–42.4, P <0.001).
Conclusion
The long-term use of nucleotide analogs increased the risk of nephrotoxicity in patients with CHB. Thus, the regular assessment of renal function is recommended for all patients with CHB, particularly those treated with a nucleotide analog.
