RESUMEN
AIM: Renal toxicity of adefovir disoproxil (ADV) and tenofovir disoproxil fumarate (TDF) is a significant concern in chronic hepatitis B (CHB) patients. Early observational clinical data suggested that telbivudine (LdT) might have renoprotective effects. METHODS: In this prospective study, consecutive CHB patients on combined lamivudine (LAM) + ADV/TDF were switched to LdT + ADV/TDF at recruitment and were followed up for 24 months. Estimated glomerular filtration rate (eGFR) was calculated with the modification of diet in renal disease equation. The effects of LdT on cell viability and expression of kidney injury or apoptotic biomarkers were investigated in cultured renal tubular epithelial cell line HK-2. RESULTS: Thirty-one patients (median age 55 years, 90.3% male) were recruited (54.8% TDF: 45.2% ADV). Serum HBV DNA was undetectable at all time points. Median eGFR was 70.2 (IQR 62.6-77.9) and 81.5 (IQR 63.6-99.1) mL/min/1.73 m2 at baseline and 24 months, respectively (p < 0.001). Downstaging of chronic kidney disease was observed in eight (25.8%) patients and was more common in ADV-treated compared to TDF-treated patients (7/8 vs. 1/17, p = 0.011; OR 16, 95% CI 1.643-155.766, p = 0.017). In vitro data showed that adding LdT to ADV or TDF was associated with improved cell viability and lower expression of injury and apoptotic biomarkers compared with ADV or TDF alone. Treatment was prematurely discontinued in four(12.9%) patients due to myalgia. CONCLUSIONS: Clinical and in vitro data suggest that LdT has renoprotective effects in patients on long-term ADV/TDF treatment. LdT may be considered as an adjuvant therapy in this special group of patients with renal impairment (NCT03778567).
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Tasa de Filtración Glomerular , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/efectos adversos , Insuficiencia Renal Crónica/metabolismo , Telbivudina/uso terapéutico , Tenofovir/efectos adversos , Factor de Transcripción Activador 4/efectos de los fármacos , Factor de Transcripción Activador 4/genética , Adenina/efectos adversos , Adenina/farmacología , Antivirales/farmacología , Apoptosis/efectos de los fármacos , Caspasa 12/efectos de los fármacos , Caspasa 12/genética , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Células Epiteliales , Femenino , Proteínas de Choque Térmico/efectos de los fármacos , Proteínas de Choque Térmico/genética , Receptor Celular 1 del Virus de la Hepatitis A/efectos de los fármacos , Receptor Celular 1 del Virus de la Hepatitis A/genética , Hepatitis B Crónica/complicaciones , Humanos , Técnicas In Vitro , Interleucina-18/genética , Túbulos Renales , Lamivudine/farmacología , Lipocalina 2/efectos de los fármacos , Lipocalina 2/genética , Masculino , Persona de Mediana Edad , Organofosfonatos/farmacología , Estudios Prospectivos , Sustancias Protectoras , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/complicaciones , Índice de Severidad de la Enfermedad , Tenofovir/farmacologíaRESUMEN
BACKGROUND: Contrast induced nephropathy (CIN) is the commonest cause of iatrogenic renal injury and its incidence has increased with the advent of complex endovascular procedures. Evidence suggests that ascorbic acid (AA) has a nephroprotective effect in percutaneous coronary interventions when contrast media are used. A variety of biomarkers (NGAL, NGAL:creatinine, mononuclear cell infiltration, apoptosis and RBP-4) in both the urine and kidney were assayed using a mouse model of CIN in order to determine whether AA can reduce the incidence and/or severity of renal injury. METHODS: Twenty-four BALB/c mice were divided into 4 groups. Three groups were exposed to high doses of contrast media (omnipaque) in a well-established model of CIN, and then treated with low or high dose AA or placebo (saline). CIN severity was determined by measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL):creatinine at specific time intervals. Histological analysis was performed to determine the level of mononuclear inflammatory infiltration as well as immunohistochemistry to determine apoptosis in the glomeruli by staining for activated caspase-3 and DNA nicking (TUNEL assays). Reverse transcriptase PCR (rtPCR) of mRNA transcripts prepared from mRNA extracted from mouse kidneys was also performed for both lipocalin-2 (Lcn2) encoding NGAL and retinol binding protein-6 (RBP4) genes. NGAL protein expression was also confirmed by ELISA analysis of kidney lysates. RESULTS: Urinary NGAL:creatinine ratio was significantly lower at 48 h with a 44% and 62% (204.3µg/mmol versus 533.6µg/mmol, p = 0.049) reduction in the low and high dose AA groups, respectively. The reduced urinary NGAL:creatinine ratio remained low throughout the time period assessed (up to 96 h) in the high dose AA group. In support of the urinary analysis ELISA analysis of NGAL in kidney lysates also showed a 57% reduction (12,576 ng/ml versus 29,393 ng/ml) reduction in the low dose AA group. Immunohistochemistry for apoptosis demonstrated decreased TUNEL and caspase-3 expression in both low and high dose AA groups. CONCLUSIONS: Ascorbic acid reduced the frequency and severity of renal injury in this murine model of CIN. Further work is required to establish whether AA can reduce the incidence of CIN in humans undergoing endovascular procedures.