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      Tenofovir disoproxil fumarate-associated renal tubular dysfunction: noninvasive assessment of mitochondrial injury

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          Abstract

          Objective:

          To determine whether tenofovir disoproxil fumarate (TDF)-associated renal tubular dysfunction is associated with evidence of mitochondrial injury in urine.

          Design:

          Single-centre cross-sectional observational study of HIV-positive outpatients.

          Methods:

          Biochemistry was performed on paired serum and urine samples. Mitochondrial DNA (mtDNA) was studied by real-time PCR and long-range PCR on cellular fractions of urine.

          Results:

          In total, 48 study participants were enrolled of whom half were TDF treated. Mean age was 43 years. 58% had estimated glomerular filtration rate at least 90, with no differences between ART treatment groups. Urinary phosphate wasting was common and independently associated with TDF exposure ( P = 0.02). No study participants had low molecular weight proteinuria. Cellular mtDNA content in urine was heavily influenced by the cellularity of the sample. The mtDNA ‘common deletion’ mutation was detectable significantly more commonly in the urine of TDF exposed study participants compared with unexposed (13/22 TDF + study participants (59%), 4/21 TDF (19%), P = 0.01). Common deletion levels were not associated with age, estimated glomerular filtration rate, or urinary phosphate wasting. No mtDNA measures were associated with current or nadir CD4 + lymphocyte counts, duration of disease or antiretroviral therapy, or historical exposure to nucleoside analogue reverse transcriptase inhibitors with systemic mitochondrial toxicity.

          Conclusion:

          The presence of mtDNA mutations in the context of TDF exposure adds weight to the hypothesis that TDF-associated renal damage is at least in part mitochondrially mediated. The assessment of mtDNA markers in urine may be a feasible noninvasive investigation for TDF-treated patients.

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          Most cited references17

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          Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age.

          We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67-77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing.
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            What causes mitochondrial DNA deletions in human cells?

            Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication. This conclusion has important implications for prevention of mtDNA disease and, potentially, for our understanding of the aging process.
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              Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients.

              Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non-HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.
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                Author and article information

                Journal
                AIDS
                AIDS
                AIDS
                AIDS (London, England)
                Lippincott Williams & Wilkins
                0269-9370
                1473-5571
                1 June 2017
                11 May 2017
                : 31
                : 9
                : 1297-1301
                Affiliations
                [a ]Wellcome Trust Centre for Mitochondrial Research
                [b ]Institute of Genetic Medicine, Newcastle University
                [c ]Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
                Author notes
                Correspondence to Brendan A.I. Payne, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. E-mail: Brendan.Payne@ 123456ncl.ac.uk
                Article
                AIDS-D-16-01153
                10.1097/QAD.0000000000001466
                5427982
                28323756
                5edf4954-7b9a-4ef7-aba1-b97ab07adfa3
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                History
                : 12 December 2016
                : 2 March 2017
                : 2 March 2017
                Categories
                Clinical Science: Concise Communications
                Custom metadata
                TRUE

                antiretroviral therapy,biomarkers,dna,fanconi syndrome,hiv,mitochondrial,renal insufficiency,tenofovir

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