RESUMEN
Little evidence is available for the incidence of chronic kidney disease (CKD) and rate of estimated glomerular filtration rate (eGFR) decrement among Asians with low body weight who are susceptible to tenofovir disoproxil fumarate (TDF) nephrotoxicity. In this 12-year observational cohort in Tokyo, we examined 1383 treatment-naïve HIV-1-infected Asians [720 started TDF-containing (TDF group) and 663 started non-TDF-containing (control) combination antiretroviral therapy (cART)]. The CKD incidence was calculated, and the effect of TDF use on CKD development was estimated using logistic regression. The eGFR slopes, before and after cART initiation, were estimated using mixed-effects linear spline models. Most patients were males (median weight, 62.6 kg; 83% started ritonavir-boosted protease inhibitors; median observation duration, 5.08 years). CKD developed in 150 patients (10.8%), with an incidence of 20.6 per 1000 person-years [confidence interval (95% CI), 17.6-24.2]. None developed end-stage renal disease. TDF use was associated with CKD [odds ratio (OR), 1.8; 95% CI, 1.00-3.13; p = 0.052]. The cumulative mean loss in the TDF group, relative to the control, increased over time after 1, 4, and 8 years of TDF exposure (-3.8, -5.5, and -9.0 mL/min/1.73 m2, respectively; p < 0.0001). The eGFR rapidly declined during the first 3 months of cART, particularly in the TDF group (-26.4 vs. -7.4 mL/min/1.73 m2/year in the control). In the TDF group, cART introduction was significantly associated with a faster rate of eGFR decline (from -0.44 to -2.11 mL/min/1.73 m2/year; p = 0.010), whereas in the control, the difference was not significant. For HIV-1-infected Asian patients with low body weight, TDF-containing cART is associated with CKD and faster eGFR declines.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Renal Crónica/inducido químicamente , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Tenofovir/efectos adversos , Adulto , Fármacos Anti-VIH/uso terapéutico , Pueblo Asiatico/estadística & datos numéricos , Peso Corporal , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Incidencia , Masculino , Inhibidores de Proteasas/uso terapéutico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etnología , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Ritonavir/uso terapéutico , Tenofovir/uso terapéutico , TokioRESUMEN
OBJECTIVE: In nephrotoxicity induced by tenofovir disoproxil fumarate (TDF), tubular dysfunction precedes the decline in GFR, suggesting that tubular markers are more sensitive than estimated glomerular filtration rate (eGFR). The hypothesis that urinary ß2 microglobulin (ß2âM), a tubular function marker, can predict TDF-renal dysfunction in HIV-1-infected patients was tested. DESIGN: A single-center observational study. METHODS: The inclusion criteria were: HIV-1-infected patients who started TDF-containing antiretroviral therapy from 2004 to 2013, urinary ß2âM after and closest to the day of TDF initiation within 180 days (termed 'ß2âM after TDF') was measured. The associations between 'ß2âM after TDF' and four renal end points (>10âml/min per 1.73âm decrement in eGFR relative to baseline, >20 decrement, >25% decrement, and eGFRâ<â60) were estimated with logistic regression model. The association between 'ß2âM after TDF' and longitudinal changes in eGFR after initiation of TDF was estimated with a mixed-model. RESULTS: A total 655 study patients were analyzed (96% men, median age 38, median CD4 238 cells/µl, 63% treatment naïve). The median baseline eGFR was 117âml/min per 1.73âm (IQR 110-125), and the median duration of TDF use was 3.32 years (IQR 2.02-5.31). 'ß2âM after TDF' was significantly associated with more than 20 decrement in eGFR (Pâ=â0.024) and more than 25% decrement (Pâ=â0.014), and was marginally associated with eGFR less than 60 (Pâ=â0.076). It was also significantly associated with the longitudinal eGFR after initiation of TDF (Pâ<â0.0001). 'ß2âM after TDF' of 1700âµg/l was identified as the optimal cutoff value for the prediction of longitudinal eGFR. CONCLUSIONS: Urinary ß2âM measured within 180 days after initiation of TDF predicts renal dysfunction related to long-term TDF use.
Asunto(s)
Antivirales/efectos adversos , Biomarcadores/orina , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Insuficiencia Renal/diagnóstico , Tenofovir/efectos adversos , Microglobulina beta-2/orina , Adulto , Antivirales/administración & dosificación , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Insuficiencia Renal/patología , Tenofovir/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement. METHODS: This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m2) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays. RESULTS: 95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/µl, median baseline eGFR of 96ml/min/1.73m2 (IQR 84.6-109.2), and median exposure to TDF of 3.66 years (IQR 1.93-5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results. CONCLUSIONS: SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.