Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion

Tanji, Nozomu; Tanji, Kurenai; Kambham, Neeraja; Markowitz, Glen S.; Bell, Alvin; D’Agati, Vivette D.

doi:10.1053/hupa.2001.25586

Cited by 187 publications

(130 citation statements)

References 16 publications

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“…Other nucleotide analogues, such as cidofovir and adefovir, may induce renal damage as a result of mitochondrial DNA depletion in renal tubular cells [25]. Cell culture studies have shown TDF to be only minimally toxic to renal tubular cells [26].…”

Section: Discussionmentioning

confidence: 99%

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

et al. 2006

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BackgroundTenofovir disoproxil fumarate (Tenofovir DF, TDF), the first nucleotide reverse transcriptase inhibitor approved for the treatment of HIV disease, has been associated with renal dysfunction in isolated cases. The aim of this study was to assess changes in renal parameters in individuals receiving TDFand non-TDF-containing highly active antiretroviral therapy (HAART). MethodsAll individuals on HAART attending our clinic were included in the analysis. Time-weighted changes in serum creatinine, calculated creatinine clearance (CCrCl) and anion-gap were assessed for individuals on TDF-and non-TDF HAART. ResultsOf 948 individuals on HAART, 290 (31%) and 618 (65%) were on TDF-and non-TDF HAART, with 40 (4%) having ceased TDF HAART. Baseline values for serum creatinine, CCrCl and anion-gap were similar for those on TDF-and non-TDF HAART. In a multivariate analysis, statistically significant differences were observed in time-weighted change from baseline in anion-gap and CCrCl between individuals on TDF-and non-TDF HAART [mean difference in change between groups: anion-gap 0.78 mmol/L (standard error, 0.19) and CCrCl À 6.80 (standard error 2.2); P 5 0.005 and P 5 0.032, respectively] after adjusting for baseline anion-gap and CCrCl, respectively. Two cases of TDF-associated renal failure were observed. ConclusionOvert renal failure with TDF HAART is rare. However, subtle but statistically significant changes in anion-gap and CCrCl were observed which were associated with TDF HAART. These parameters may be of use in monitoring individuals on HAART. Cidofovir and adefovir, compounds structurally related to TDF, have been associated with an increased risk of acute renal insufficiency. In particular, a dose-and timedependent development of a Fanconi-like syndrome has been reported [5,6]. In pivotal studies assessing the safety and efficacy of TDF, renal safety profiles were found to be similar in individuals receiving and in those not receiving TDF-containing highly active antiretroviral therapy (HAART) [2][3][4]. In addition, a recent large cohort has described no significant evidence of renal dysfunction with the use of TDF in clinical practice [7]. However, there are mounting numbers of anecdotal reports describing Fanconi's syndrome and renal insufficiency induced by TDF therapy [8][9][10][11][12][13][14][15][16][17][18]. Predisposing factors for the development of acute renal failure with the use of TDF remain obscure.Several groups reporting no significant evidence of renal dysfunction with the use of TDF have relied on serum creatinine as a marker of renal function [7]. A recent report utilizing glomerular filtration rate (GFR) calculated on the basis of a 24-h urine collection has observed a lower GFR associated with TDF treatment [19].The aim of this study was to investigate changes in anion-gap and calculated creatinine clearance (CCrCl) in a large cohort of HIV-1-infected individuals receiving TDFand non-TDF-containing HAART. Methods Study designAll individuals currently on HAART attending the Departmen...

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Section: Discussionmentioning

confidence: 99%

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

et al. 2006

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“…Mouse monoclonal antibodies (Molecular Probes Inc, Eugene, OR, USA) raised against human COX subunit I (clone 1D6) which is mtDNA encoded and human COX subunit IV (clone 20E8), which is nDNA encoded were used. 16 A three step avidinbiotin immunoperoxidase method with prior heatinduced antigen retrieval (TRS, Dako, Trappes, France) was performed on formalin-fixed paraffinembedded liver biopsy sections. Labeling of COX subunits was assessed by three observers (JPDVH, MFB, and PB) in a blinded fashion.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…[12][13][14][15] In this regard, various antibodies raised against proteins involved in mitochondrial oxidative phosphorylation are now available for immunohistochemistry on formalin-fixed paraffin-embedded tissues. 16 In the present study, the immunohistochemical detection of respiratory chain protein cytochrome oxidase (COX) subunits I and IV, encoded by mtDNA and nuclear DNA (nDNA), respectively, was performed in liver biopsies from HIV patients. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy.…”

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confidence: 99%

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients

et al. 2006

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Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.

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“…ADV-induced FS is postulated to result from the inhibition of DNA polymerase (required for mitochondrial DNA replication) after entrance into renal tubular cells through human renal organic anion transporter-1 (hOAT-1), causing adenosine triphosphate (ATP) depletion [16]. ATP depletion may then alter the activities of membrane transporters causing urinary solute loss.…”

Section: Discussionmentioning

confidence: 99%

Adefovir-induced Fanconi syndrome: diagnostic pearls and perils of late or missed diagnosis

et al. 2014

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Low-dose adefovir therapy has been increasingly recognised as a cause of Fanconi syndrome. Being relatively novel, early diagnosis is both fraught with difficulty and yet of paramount importance given its farreaching consequences, many of which are amenable to treatment. We discuss a patient who presented with hypokalemia and other electrolyte abnormalities suggestive of Fanconi syndrome whilst on adefovir for hepatitis B. A trans-tubular potassium gradient (TTKG = 9.4) and urinary fractional phosphate excretion (39.4 %) consistent with renal potassium and phosphate wasting together with euglycemic glycosuria, aminoaciduria and hypophosphatemic osteomalacia supported the diagnosis of adefovirinduced Fanconi syndrome. With the cessation of the culprit drug, the patient has achieved partial recovery after 9 months. A high index of suspicion coupled with regular symptom surveillance and electrolyte monitoring is recommended in the course of adefovir therapy.

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Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion

Cited by 187 publications

References 16 publications

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients

Adefovir-induced Fanconi syndrome: diagnostic pearls and perils of late or missed diagnosis

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