Article

Tenofovir-associated renal and bone toxicity

The Mortimer Market Centre, Camden PCT, London, UK.
HIV Medicine (Impact Factor: 3.99). 06/2009; 10(8):482-7. DOI: 10.1111/j.1468-1293.2009.00716.x
Source: PubMed

ABSTRACT

The aims of the study were to describe the clinical presentation and renal and bone abnormalities in a case series of HIV-infected patients receiving treatment with tenofovir (TDF), and to recommend appropriate screening for toxicity related to TDF.
Patients were identified from referrals to a specialist HIV renal clinic. Patients were included if treatment with TDF was assessed as the primary cause of the renal function impairment and clinical data were available prior to and following discontinuation of TDF treatment. Data were collected from case note review and clinic databases.
Twenty-two patients (1.6% of all those who received TDF) were identified with TDF-associated renal toxicity. All had normal serum creatinine prior to TDF therapy. All presented with proteinuria. On stopping TDF, renal function improved. Eight patients had confirmed Fanconi syndrome. Twelve patients presented with bone pain and osteomalacia was confirmed on an isotope bone scan in seven of these patients. The findings (in those patients tested) of tubular proteinuria, reduced tubular transport maximum of phosphate (TmP), and glycosuria were all consistent with the proximal tubule being the site of toxicity.
Renal toxicity remains a concern in patients treated with TDF. Clinical presentation may be with renal dysfunction, Fanconi syndrome or osteomalacia. Our investigations suggest proximal tubular toxicity as a common pathogenic mechanism.

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Available from: Devaki R Nair, Jan 04, 2015
    • "The most frequent tubular abnormality was a lower reabsorption of phosphate. Previous in-vitro studies have suggested that phosphate transport in the proximal tubule is particularly sensitive to mitochondrial toxicity[34], and increased urinary phosphate excretion has been previously associated with TDF use[6,14,35,36]. We observed a clear association between phosphaturia and eGFR decline, and a significant correlation with phosphatemia. "
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    ABSTRACT: Objectives: Patients receiving tenofovir, disoproxil, fumarate (TDF) had an increased prevalence of proximal renal tubular dysfunction (PRTD), but contributing factors and its clinical significance remain controversial. Design and methods: Cross-sectional evaluation of different urinary parameters (proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria) in 200 HIV-infected patients receiving TDF, 26 following TDF discontinuation, and 22 never treated with TDF, included in a prospective cohort study. PRTD was defined as two or more tubular abnormalities. Results: After a median of 65 months (interquartile range, 42.7–84.7), at least one tubular alteration was found in 72% of patients, mostly proteinuria (42, 50, and 14% in current, previous and never TDF use; P=0.02) and phosphaturia (46, 42, and 14%; respectively, P < 0.01). PRTD was found in 63 patients (32%) receiving TDF, ranging from 14 to 46% according to concomitant hepatitis C virus coinfection, diabetes mellitus or hypertension arterial, in contrast with six (23%) following TDF discontinuation, and zero cases in no TDF-treated patients. The use of TDF [odds ratio (OR) 13.2; 95% confidence interval (CI) 1.4–22.7; P = 0.01], cumulative time on combination antiretroviral therapy (OR 1.011; 95% CI 1.07–1.019 per month; P = 0.01), and baseline estimated glomerular filtration rate (eGFR, OR 0.97; 95% CI 0.94–0.99 per ml/min per 1.73 m2 higher; P = 0.04) were associated with PRTD. The number of tubular abnormalities was linearly associated with eGFR decline since TDF initiation (β-coefficient –0.15, P = 0.02), together with age (–0.18; P = 0.01), baseline eGFR (0.49, P = 0.01), diabetes mellitus (–0.19, P = 0.02), and time on TDF (–0.23; P = 0.01). Conclusion: The use of TDF leads to an increased rate of tubular dysfunction, and modulated by age, baseline eGFR, and classical factors, is associated with kidney function decline.
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    • "In the TDF treated HIV patients who underwent kidney biopsy, the main abnormality on light microscopy was acute proximal tubule damage, and the presence of intracytoplasmic inclusions. Electron microscopy showed widespread morphologic abnormalities in proximal tubule mitochondria, with marked variations in size and shape , disruption of cristae, mitochondrial swelling, and intra-mitochondrial deposits [7,14]. "
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    ABSTRACT: Nephrotoxicity is a dose limiting side effect of tenofovir, a reverse transcriptase inhibitor that is used for the treatment of HIV infection. The mechanism of tenofovir nephrotoxicity is not clear. Tenofovir is specifically toxic to the proximal convoluted tubules and proximal tubular mitochondria are the targets of tenofovir cytotoxicity. Damaged mitochondria are major sources of reactive oxygen species and cellular damage is reported to occur after the antioxidants are depleted. The purpose of the study is to investigate the alterations in cellular antioxidant system in tenofovir induced renal damage using a rat model. Chronic tenofovir administration to adult Wistar rats resulted in proximal tubular damage (as evidenced by light microscopy), proximal tubular dysfunction (as shown by Fanconi syndrome and tubular proteinuria), and extensive proximal tubular mitochondrial injury (as revealed by electron microscopy). A 50% increase in protein carbonyl content was observed in the kidneys of TDF treated rats as compared with the control. Reduced glutathione was decreased by 50%. The activity of superoxide dismutase was decreased by 57%, glutathione peroxidase by 45%, and glutathione reductase by 150% as compared with control. Carbonic Anhydrase activity was decreased by 45% in the TDF treated rat kidneys as compared with control. Succinate dehydrogenase activity, an indicator of mitochondrial activity was decreased by 29% in the TDF treated rat kidneys as compared with controls, suggesting mitochondrial dysfunction CONCLUSION: Tenofovir- induced mitochondrial damage and increased oxidative stress in the rat kidneys may be due to depletion of the antioxidant system particularly, the glutathione dependent system and MnSOD.
    Full-text · Article · Aug 2013 · Journal of Biomedical Science
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    • "The absence of a significant association between raised RBPCR and TFV exposure in general, or TFV/PI exposure more specifically, may relate to the fact that our patients had no evidence of clinical renal tubular toxicity, the size and heterogeneity of the cohort, the assay or the RBPCR cut-off chosen for our analyses, or unmeasured confounding. Of note, the median RBPCR in a previous study of patients with TFV-induced Fanconi syndrome was 5593 μg/mmol (49,515 μg/g) [21], which is approximately 100-fold higher than the upper limit of the reference range of the assay used in our study. As almost all of our patients had RBPCR measurements within (or slightly above) the reference range, RBPCR appears to have good discriminatory value between severe, treatment-limiting renal tubular disease and normal tubular function or mild, asymptomatic renal tubular dysfunction. "
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    ABSTRACT: Chronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients. In a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI). Proteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR. In HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.
    Full-text · Article · Aug 2012 · BMC Nephrology
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