Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients

Casado, José L.; Santiuste, Carmen; Vázquez, M Díaz; Bañón, Sara; Rosillo, Marta; Gómez, Ana; Pérez-Elías, María Jesús; Caballero, Carmen; Rey, José Manuel del; Moreno, Santiago

doi:10.1097/qad.0000000000001067

Cited by 58 publications

(51 citation statements)

References 35 publications

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“…We observed a significantly higher prevalence of bone disease in patients with signs of KTD when compared with patients without KTD (54,8 vs 27,6%; p = 0.002 ) and a strong association between bone disease an KTD was also confirmed in the multivariable analysis. As previously described in HIV positive patients treated with TDF a strong association was observed between KTD and a lower bone mineral density [21, 22]. In addition the prevalence of bone disease (osteopenia/osteoporosis) such as the prevalence of KTD was similar to previous report by Calmy et al [23].…”

Section: Discussionsupporting

confidence: 89%

Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

et al. 2017

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BackgroundTenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes.MethodsWe retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (−24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis.ResultsOne hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with “GG” genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of “G” allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25–17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529–6.603, p = 0.002).ConclusionsAccording to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed.

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Section: Discussionsupporting

confidence: 89%

Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

et al. 2017

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“…However, its clinical significance remains unclear because we neither measured ionized calcium nor corrected for hypoalbuminaemia. Although we did not observe TDF use or TDF-induced secondary hyperparathyroidism to be associated with renal phosphate wasting -a potential mechanism of bone demineralization [15,31,32], we could not rule out this condition because we lack information on renal phosphate loss that could be measured in a 24-h urine specimen or calculated as the ratio of renal tubular maximum reabsorption of phosphate to GFR [33].…”

Section: Discussionmentioning

confidence: 90%

Impact of Tenofovir Disoproxil Fumarate on Bone Metabolism and Bone Mass among Perinatally HIV-Infected Asian Adolescents

et al. 2016

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“…After a long-term follow-up study, we did not detect the emergency of TDF-resistance-associated variants (rtA194T, rtP177G, and rtF249A) [7, 8], suggesting that this study will provide the basis for changing to a different medication in clinical trials. The research also revealed bone loss caused by proximal tubular dysfunction during TDF therapy [25, 26], so longitudinal follow-up studies are needed.…”

Section: Discussionmentioning

confidence: 99%

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

Zhang

et al. 2016

Oncotarget

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AimsThe dynamics of resistance-associated mutations under combination therapy were explored.MethodsA total of 46 patients were classified into adefovir (n=14) and entecavir (n=32) groups. In the adefovir (ADV) group, six patients receiving combined therapy were DNA-positive after more than 3 years of therapy. Ultra-deep pyrosequencing was used to analyze the dynamics of multi-drugs resistance mutations.ResultsAt baseline, all 46 treatment-naïve patients harbored rtA181V/T substitutions (1.2%-4.6%) and rtN236T substitutions (1.6%-6.1%). In the ADV group, eight patients with long-term treatment were consecutively HBV DNA-positive for more than 3 years. During treatment, the rtA181T resistance-associated site appeared with increasing frequency in six of eight patients (NOs. 1-6), and two patients (NOs.4 and 8) carrying the rtA181T resistance mutations increasingly showed high levels of rtN236T. One patient (NO. 8) experienced virological breakthrough. Other known pre-existing mutations showed no dynamic fluctuations, including in rtA194T, rtP177G, rtF249A, and rtD263E. In addition to the common substitutions, some previously unknown amino acid substitutions, such as rtD134N, rtL145M/S, rtF151Y/L, rtR153Q, and rtS223A, should be further studied.ConclusionsHBV-resistance substitutions conferring to nucleoside analogs are present at baseline. The dynamics of the HBV RT-region quasispecies variation are heterogeneous and complex.

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Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients

Abstract: Chronic abnormal phosphaturia explains, at least in part, progressive bone loss during TDF therapy. These data suggest that tubular dysfunction leads to an altered equilibrium between phosphataemia, phosphaturia, and bone as mechanism of progressive BMD decline.

Cited by 58 publications

References 35 publications

Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

Impact of Tenofovir Disoproxil Fumarate on Bone Metabolism and Bone Mass among Perinatally HIV-Infected Asian Adolescents

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

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