Early Kidney Injury During Long-term Chronic Adefovir Dipivoxil Therapy In Patients With Hepatitis B

BackgroundHepatitis B virus (HBV) infects more than 350 million people worldwide. Hepatitis B is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). High level of HBV DNA is an independent factor associated with liver cirrhosis, HCC. Therefore, the main goal of treatment is complete suppression of HBV replication to limit progressive liver damage and improve natural history of chronic hepatitis B (CHB). Currently, oral nucleos(t)ide analogs (NAs) have demonstrated success in suppressing virus replication, with few side effects. Evidence-based medicine has demonstrated that a slow virological response after initiation of NA treatment is associated with high rates of drug resistance in the long term.Among the available NAs, adefovir dipivoxil (ADV) is a phosphonate acyclic nucleotide analog of AMP. It is a potent inhibitor of HBV reverse transcriptase and is effective for patients with hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. ADV also has the characteristic of no cross-resistance with other nucleoside analogs such as lamivudine (LAM), telbivudine (LdT) and entecavir (ETV). So, it is widely used in rescue therapy for LAM, LdT and ETV resistance. However, renal dysfunction associated with prolonged use of ADV has been reported recently. 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 months. However, most routine renal function tests used in these studies were based on serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate (eGFR). These biomarkers were outdated because they failed to identify early stages of renal dysfunction and structural injury. Therefore, the finding of a reliable and sensitive biomarker of early diagnosis of renal dysfunction would be helpful in facilitating early intervention, and evaluating the effectiveness of therapeutic intervention for CHB patients.β2-Microglobulin(β2-M) is an 11.8-kDa protein, which is a light chain of major histocompatibility class (MHC) I expressed on the surface of every nucleated cell. Rentinol binding protein (RBP) is a protein of 21 kDa, which is synthesized by the liver. Both β2-M and RBP subject to glomerular filtration, and most undergoes proximal tubular reabsorption and catabolism, which might be disrupted in renal dysfunction. β2-M and RBP excretion in urine has been reported as an early marker of nephrotoxicity induced by nephrotoxic substances, cardiac surgery, diabetes mellitus, or hypertension. At present, it remains unclear whether urine β2-M and RBP can be used as early markers to diagnose renal impairment in CHB patients with long-term ADV treatment.In this study, we aimed to evaluate the relationship between urine β2-M and RBP excretion and early renal impairment during long-term ADV treatment in CHB patients.MethodsWe enrolled 165 CHB patients who were treated with ADV monotherapy (n=90) or ADV plus lamivudine (LAM) combination therapy (n=75). Another 165 CHB patients treated with entecavir (ETV) were recruited as controls. We detected serum creatinine, estimated glomerular filtration rate (eGFR), urine β2-M and RBP level at initiation of antiviral therapy and every 6 months.ResultThree,7,11,16 and 21 patients developed urine β2-M abnormality in the first, second, third, fourth and fifth year of treatment, respectively. Two,8,12,15 and 22 patients developed urinary RBP abnormality in the first, second, third, fourth and fifth year of treatment, respectively. eGFR decreased 20-30% from baseline in 20 patients, 30-50% in 12, and>50% in 3(1.8%) in patients during the 5 years of treatment. Further analysis indicated that decreases in eGFR of≥30% relative to the baseline level in 5 years correlated significantly with urine RBP and β2-M abnormality. While both serum creatinine and eGFR remained stable, only one patient developed urine β2-M abnormality and two developed urine RBP abnormality during the 5 years of ETV treatment.ConclusionsUrine RBP and β2-M were sensitive biomarkers of early renal injury during long-term ADV treatment. ADV should be switched to ETV immediately as soon as urine RBP or p2-M is detected. ADV should be avoided as first-line treatment for CHB.