Effects of renal tubular dysfunction on bone in tenofovir-exposed HIV-positive patients

Hamzah, Lisa; Samarawickrama, Amanda; Campbell, Lucy; Pope, Matt; Burling, Keith; Walker‐Bone, Karen; Gilleece, Yvonne; Fisher, Martin; Post, Frank A.

doi:10.1097/qad.0000000000000760

Cited by 33 publications

(30 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 88%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 88%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Pregnancy and exposure to exogenous estrogen are associated with significant increases DBP levels [21]. DBP levels are lowered in the setting of chronic liver disease due to decreased synthesis of DBP, chronic kidney disease due to increased renal losses, and in type 1 diabetes mellitus [22-4]. A few studies have found that DBP levels are decreased among adults and children in acute inflammatory states such as critical illness, sepsis, or following surgery, possibly due to increased urinary losses of DBP or increased actin binding to protect against polymerization of actin released from damaged tissue [25-7].…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanisms underlying these associations remain unclear. Proposed mechanisms for these changes include toxicity of the proximal renal tubular cells causing urinary phosphate wasting, alterations of calcium and phosphate homeostasis, and osteomalacia [3,4]. However cases of Fanconi’s syndrome are rare and osteomalacia from clinically significant hypophosphatemia is relatively uncommon among patients receiving TDF, and does not seem to sufficiently account for the degree of bone loss and fracture reported [5,6].…”

Section: Introductionmentioning

confidence: 99%

Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV

Hsieh

Fraenkel

Han

et al. 2016

Aids

View full text Add to dashboard Cite

Objective To examine longitudinal change in vitamin D binding protein (DBP) levels during the first year after initiation of tenofovir (TDF)/lamivudine (3TC)/efavirenz (EFV), and compare these findings to concurrent changes in markers of skeletal metabolism. Design Secondary analysis of plasma samples collected from an ongoing multi-center clinical trial. Methods Plasma samples collected at 0, 24, and 48 weeks after initiation of TDF+3TC+EFV from 134 adult participants enrolled in a multi-center randomized trial were analyzed. Data regarding socio-demographic and clinical characteristics were obtained as part of the parent study. Laboratory analyses included plasma DBP, intact parathyroid hormone (iPTH), total 25-hydroxyvitamin D (25OHD), phosphorus, the bone resorption marker collagen type 1 cross-linked C-telopeptide, and the bone formation marker total procollagen type 1 N-terminal propeptide. Repeated measures ANOVA was used to measure change in biomarkers over time. Results Our sample included 108 men and 26 women (mean age 33.6±9.6 yrs). Median levels of DBP increased significantly from baseline to 48 weeks [154(91.8-257.4) v. 198.3(119.6-351.9) μg/mL, p<0.001]. A concurrent rise in iPTH levels was observed over the same period [32.3(24.4-40.9) v. 45.2(35.1-60.4) pg/mL, p<0.001), however 25OHD and phosphorus levels remained stable. Bone resorption and formation markers increased rapidly from 0 to 24 weeks, followed by a slight decline or plateau, but remained significantly elevated at 48 weeks (p<0.001). Conclusion Our study provides longitudinal data supporting a potential role for DBP in bone loss associated with TDF-based therapy. Further research to elucidate the mechanistic pathways and clinical impact of these findings is warranted.

show abstract

“…The nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been linked with increased PTH levels, phosphate wasting by the kidney and low BMD in treated HIV-infected patients(48–51), but there is no direct evidence that this occurs through alterations in vitamin D metabolism. However, vitamin D status may modify the effect of TDF on PTH levels(48, 52) and on BMD(47*).…”

Section: Vitamin D Deficiency In Hivmentioning

confidence: 99%

Vitamin D and bone loss in HIV

Hileman

Overton

McComsey³

2016

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

Purpose of review Bone health has become an increasingly important aspect of the care of HIV-infected patients as bone loss with antiretroviral therapy (ART) initiation is significant and osteopenia and osteoporosis are highly prevalent. Vitamin D is tightly linked to calcium balance and bone health and vitamin D deficiency is common in HIV. This review outlines the epidemiology of vitamin D deficiency in HIV, summarizes our current understanding of the relationship between vitamin D and bone loss in HIV and the impact of vitamin D supplementation in this patient group. Recent findings While data are conflicting as to whether vitamin D deficiency is more prevalent among HIV-infected individuals than in the general population, there are several reasons for why this patient group may be at heightened risk. Studies linking vitamin D deficiency to bone loss in HIV are limited; however, data from randomized clinical trials suggest a benefit of vitamin D supplementation for the prevention of bone loss with ART initiation and for the treatment of bone loss with bisphosphonate therapy. Summary There are too limited data to recommend universal screening of vitamin D status or supplementation to all HIV-infected individuals. However, testing 25-hydroxyvitamin D levels in those at risk for deficiency and treating patients found to be deficient or initiating antiretroviral therapy or bisphosphonate therapy should be considered. Further study on vitamin D supplementation is needed regarding the potential benefit on immune activation and restoration in this patient group.

show abstract

Effects of renal tubular dysfunction on bone in tenofovir-exposed HIV-positive patients

Abstract: In HIV-positive patients receiving TDF-containing antiretroviral therapy, RTD was associated with lower BMD of the spine in HIV-positive men. RBPCR quantification may identify patients at increased risk of TDF-associated BMD loss.

Cited by 33 publications

References 36 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

Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV

Vitamin D and bone loss in HIV

Contact Info

Product

Resources

About