Adefovir (ADV) was approved for the treatment of chronic hepatitis B (CHB) in 2002 and launched in China in 2005. By 2008, the number of people taking ADV worldwide was approximately 410,000/year. 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 ADV 10mg/d is usually considered safe, but in recent years, it has been reported in the literature that 10mg/d in the treatment of CHB can also cause nephrotoxicity, mainly proximal renal tubular damage, which can manifest as Fanconi syndrome. 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.
ADV nephrotoxicity is mainly related to the following factors.
(1) dose and duration of administration.
(2) previous history of kidney injury.
(3) Combined use of nephrotoxic drugs.
(4) Children, elderly or low weight individuals.
(5) Genetic factors.
Mechanism of renal damage of nucleotides
ADV-induced proximal tubular lesions are thought to be the result of direct nephrotoxicity and mitochondrial toxicity. The nephrotoxicity is mainly related to the enrichment of drug by organic anion transport protein 1 (HOAT-1) and the blocked excretion of drug by multidrug resistance-associated protein 2 (Mrp2) in human proximal tubules.
Mrp2 is an ATP-dependent drug efflux pump localized 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 drug concentration in the proximal tubule, and increase nephrotoxicity. The mechanism of TFV renal damage is similar to that of ADV.
Clinical manifestations of Fanconi syndrome caused by nucleoside analogues
1. Symptoms and signs: all patients had bone pain and 5 cases were associated with decreased muscle strength.
2. Fanconi syndrome is a renal tubular dysfunction disease, mainly caused by damage to the proximal tubular epithelial cells of the composite transport dysfunction, with prominent loss of urinary glucose, amino acids, phosphate and uric acid, but also loss of small molecule protein and electrolytes, which can cause hypophosphatemia, hypokalemia, hypocalcemia and osteoporosis.
Adult-acquired Fanconi syndrome is often characterized by osteoporosis.
Diagnosis and differential diagnosis of Fanconi syndrome caused by nucleotides
1. History of taking nucleotides.
Clinical manifestations: insidious onset, no obvious symptoms in the early stage, bone pain is more prominent in the later stage, and there may be a decrease in muscle strength.
3. Ancillary tests: Impaired proximal renal tubular function 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 syndrome caused by Fanconi syndrome and other drugs, toxins caused by the proximal tubular damage. Recovery of renal damage after drug discontinuation also supports this diagnosis.
Treatment of Fanconi syndrome caused by nucleotides
The key is to discontinue nucleoside analogues and replace them with other types of antiviral drugs.
Some studies recommend that patients with severe hypophosphatemia should be treated with phosphorus supplementation, usually with potassium phosphate or sodium phosphate orally or intravenously, 1000 mg/d orally for mild hypophosphatemia (0.8-0.96 mmol/L) and 1000 mg/d orally or intravenously for moderate hypophosphatemia 0.3-0.8 mmol/L, (2.5-5.0 mg/kg). Severe low blood phosphorus (<0.3mmol/L) intravenous phosphorus supplementation for 2-6h (2.5-5.0mg/kg). In combination with bone disease, vitamin D 3400-1000 U/d can be administered at the same time.
Prognosis of Fanconi syndrome caused by nucleotides
The prognosis of drug-induced Fanconi syndrome is good, as the disease can be reversed after removing the cause.
Some studies have reported hypophosphatemia with proteinuria and renal impairment even after discontinuation of ADV and calcium and phosphorus supplementation.
Prevention of Fanconi syndrome caused by nucleotides
1. In view of the renal impairment of nucleotides mentioned above, patients who intend to use these drugs clinically should have a baseline assessment of renal function and calculate glomerular filtration rate (GFR) before use, and the drug should be reduced for patients with existing chronic renal insufficiency; the British HIV Association recommends that patients starting TFV should be monitored for GFR, serum phosphorus, urine test paper (urine sugar), and urine glucose every 4 weeks for the first year. polymerase chain reaction (PCR).
2. In addition, the application of drug transporter inhibitors is another way to prevent renal damage from nucleotides.