Oral anti-hepatitis B virus nucleoside (acid) analogs mainly include nucleoside analogs (lamivudine, entecavir, tipifudine, etc.) and nucleotide analogs (adefovir, tenofovir, etc.). Among them, nucleotide analogues are excreted from the body in the proximal tubular epithelial cells after filtration by the glomerulus in their original form and are prone to accumulate in the proximal tubular epithelium, thus producing nephrotoxicity. Adefovir (ADV) was approved for the treatment of chronic hepatitis B (CHB) in 2002 and launched in China in 2005, and by 2008, the number of people taking ADV worldwide was approximately 410,000/year.
By 2008, about 410,000 people/year were taking ADV worldwide. Tenofovir (TFV) for the treatment of CHB in adults is currently in phase III clinical trials in China and will soon be approved for use in China. The dose of 10 mg/d of ADV is generally considered safe, but in recent years, there have been some reports of the use of tenofovir in adults with CHB.
However, in recent years, it has been reported in the literature that 10 mg/d in the treatment of CHB can also cause nephrotoxicity, mainly proximal tubular damage, which can manifest as Fanconi syndrome.
Renal damage has also been reported with TFV. Therefore, nephrotoxicity of nucleotides has become a problem that cannot be ignored, and clinicians need to raise awareness of nephrotoxicity of these drugs for early detection and early treatment. According to the literature, ADV
nephrotoxicity is mainly related to the following factors: (1) dose and duration of administration; (2) previous history of renal injury; (3) combination of nephrotoxic drugs; (4) children, elderly or low weight individuals; (5) genetic factors. Nucleotide drugs are mainly excreted by the active secretion of the renal tubules, which can easily cause damage to the renal tubules.
The proximal tubular lesions caused by ADV are thought to be due to direct nephrotoxicity and mitochondrial toxicity. The nephrotoxicity is mainly related to the drug enrichment by organic anion transport protein 1 (HOAT-1) and multidrug resistance-associated protein 2 (Mrp2) excretion in human proximal tubules.
The nephrotoxicity is mainly related to the drug enrichment by organic anion transport protein 1 (HOAT-1) and the blockage of drug excretion by multidrug resistance-associated protein 2 (Mrp2) in human proximal tubules. HOAT-1 has a strong affinity for nucleotide analogs and can actively uptake ADV, resulting in high concentrations in the proximal tubule.
Mrp2 is an ATP-dependent drug efflux pump located at the parietal side of the proximal tubule, which mainly mediates the active secretion of ADV out of the body, and drug competition can reduce the efflux of ADV, increase the concentration of drugs in the proximal tubule, and increase the nephrotoxicity.
The mechanism of TFV renal damage is similar to that of ADV. Clinical manifestations of Fanconi syndrome caused by nucleotides 1. Symptoms and signs: all patients had bone pain and 5 cases had decreased muscle strength. 2.
Fanconi syndrome is a renal tubular dysfunctional disease, mainly caused by damage to the proximal tubular epithelial cells, which results in a complex transport dysfunction, with prominent loss of urinary glucose, amino acids, phosphate and uric acid, as well as loss of small molecules of protein and electrolytes. Adult-acquired Fanconi syndrome is often characterized by osteoporosis. Diagnosis and differential diagnosis of Fanconi syndrome caused by nucleotides 1. History of taking nucleotides. 2. Clinical manifestations: insidious onset, no obvious symptoms in the early stage, bone pain is more prominent in the later stage, and muscle strength may be reduced. 3. Ancillary tests: Impaired proximal renal tubular function manifestations such as amino aciduria, phosphaturia, renal diabetes, tubular proteinuria, hypophosphatemia, hypouricemia, hypokalemia, etc. Generally, amino aciduria, renal diabetes and phosphaturia are the basic diagnostic indicators. 4. Need to be distinguished from the following diseases: congenital genetic factors such as cystine storage disease, glycogen storage disease, Lowe
Fanconi syndrome caused by congenital genetic factors such as cystine storage disease, glycogen storage disease, Lowe syndrome, and other drugs, toxins caused by the proximal tubular injury. Recovery of renal damage after drug discontinuation also supports this diagnosis. Treatment of Fanconi syndrome caused by nucleotides There is no uniform treatment principle reported in the literature. Some studies recommend that patients with severe hypophosphatemia should be treated with phosphorus supplementation, usually with potassium phosphate or sodium phosphate orally or intravenously, with oral supplementation of 1000 mg/d for mild hypophosphatemia (0.8-0. 96 mmol/L) and 1000 mg/d for moderate hypophosphatemia.
mg/d, moderate hypophosphorus 0.3-0.8 mmol/L can be treated with 1000 mg/d orally or intravenous phosphorus supplementation for 2-6 h (2.5-5.0
mg/kg), severe hypophosphorus (<0.3 mmol/L) intravenous phosphorus supplementation for 2-6 h (2.5-5.0 mg/kg). In combination with bone disease, vitamin D3 400-1000
The prognosis of Fanconi syndrome caused by nucleotides is usually reversible after removal of the cause of Fanconi syndrome, and the prognosis is good. Some studies have reported hypophosphatemia with proteinuria and renal impairment even after discontinuation of ADV and supplemental calcium and phosphorus therapy. Prevention of Fanconi syndrome with nucleotides 1. In view of the renal damage of nucleotides mentioned above, patients who are clinically proposed to use these drugs should undergo a baseline assessment of renal function and calculate glomerular filtration rate (GFR) before use.
(The British HIV Association recommends that patients starting TFV should be monitored every 4 weeks for the first year.
GFR, serum phosphorus, urine test paper (urine glucose), and urine polymerase chain reaction (PCR) should be monitored every 4 weeks for 1 year. 2. In addition, drug transporter inhibitors are another way to prevent renal damage from nucleotide analogues.