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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e31819c20d8
Case Report

Bone Pain Due to Fractures Revealing Osteomalacia Related to Tenofovir-Induced Proximal Renal Tubular Dysfunction in a Human Immunodeficiency Virus-Infected Patient

Perrot, Serge MD, PhD*; Aslangul, Elisabeth MD, PhD*; Szwebel, Tali MD*; Caillat-Vigneron, Nadine MD†; Le Jeunne, Claire MD, PhD*

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From the *Hôpital Hôtel Dieu, Médecine Interne, Université Paris Descartes, Paris, France; and †Department of Nuclear Medicine, Hotel Dieu, Université Paris Descartes, Paris, France.

Correspondence: Dr. Serge Perrot, MD, Hôtel Dieu, 1 Place du Parvis Notre Dame, F-75004 Paris, France. E-mail: serge.perrot@htd.aphp.fr.

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Abstract

Tenofovir is a nucleoside reverse transcription inhibitor used to treat human immunodeficiency virus patients with early treatment failure. Increasing numbers of cases of tubular dysfunction and Fanconi syndrome have been reported in patients treated with tenofovir, after the detection of biochemical abnormalities during routine assessments. Some patients have acute renal failure, and bone involvement is observed in rare cases. We describe a case of chronic metabolic complications with bone fractures related to tenofovir treatment. Several factors that increased the renal toxicity of tenofovir included low body mass index, concomitant use of nonsteroidal anti-inflammatory agents, and other antiretroviral drugs, including ritonavir.

Tenofovir is a nucleoside reverse transcription inhibitor. It was released onto the market in 2001 and is particularly useful for treating human immunodeficiency virus (HIV) patients with early treatment failure. Since 2002, increasing numbers of cases of tubular dysfunction and Fanconi syndrome have been reported in patients treated with tenofovir.1–4 Most of these cases were diagnosed after the detection of biologic abnormalities during routine assessments, in the absence of bone abnormalities. We describe a case of chronic bone complications related to tenofovir treatment in which several factors increased the renal toxicity of tenofovir.

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CASE REPORT

A 51-year-old woman was referred to our rheumatology department for lower limb pain. She had been diagnosed with HIV infection 16 years ago and had been taking a combination of antiretroviral treatments (ritonavir, lamivudine, atazanavir, tenofovir) for 16 months. Her body mass index (BMI) was 18 kg/m2. Pain had come on gradually, with no triggering factor, and was felt only on movement during the 3 months preceding consultation. At the time of visit, the patient reported pain in both legs and feet, with considerable functional impairment, as demonstrated by an inability to walk more than 500 m. She had no nocturnal pain, paresthesia, or any other symptom. She had been prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) (ketoprophen, diclofenac) and morphine sulfate due to the intensity of the pain, her job as a tourist guide requiring her to be on her feet all day. Analgesics had been found to have only a weak effect. Physical examination of our patient revealed no physical abnormalities. In particular, neurologic examination showed no signs of peripheral neuropathy.

Radiographs of both legs and feet were normal, and blood analysis (sedimentation rate and C-reactive protein concentration) revealed no inflammation. Treatment of the patient’s HIV infection was effective: she had a viral load <75 RNA copies/mL and a CD4 count of 290 μL−1.

As the pain was persistent and severe, we carried out bone scintigraphy. Several zones of 99mTC-methylene diphosphonate uptake were identified in the legs and feet, and in the pelvis and ribs, consistent with bone fractures and suggesting a diffuse metabolic bone dysfunction (Figure 1). Laboratory test results were as follows: normal complete blood formula, creatinine concentration of 133 μmol/L (N: 45–110 μmol/L), and uric acid concentration of 162 μmol/L (N < 360 μmol/L in women). Creatinine clearance (Modification of Diet in Renal Disease [MDRD] method) was 39 mL/min/1.73 m.2 Further tests demonstrated severe hypophosphataemia (0.50 mmol/L [N = 0.8–1.6 mmol/L]), normal calcemia (2.24 mmol/L [N = 2.2–2.6 mmol/L]), and normal blood glucose concentration (4.9 mmol/L [N < 5.3 mmol/L]). Urine analysis revealed glycosuria (2.7 mmol/L in urine), proteinuria (2.03 g/L), calciuria (1.7 mmol/24 h [N < 0.1 mmol/kg/24 h]), phosphaturia (12 mmol/24 h [N = 10–20 mmol/24 h]) and an absence of urinary sediment, hematuria, bacteruria, or eosinophiluria. Concentrations of 25 OH vitamin D were low, at 22 nmol/L (N = 35–80 nmol/L), as were those of parathyroid hormones 1–84 (35 pg/mL [N = 10–65 pg/mL]). An analysis of bone metabolism demonstrated a high level of bone remodelling (cardiac transplantation: 15.2 nM [N = 0.7–3.0]). Test results for hepatitis B and C infections were negative. The abnormalities detected led to the diagnosis of proximal tubulopathy, associated with severe renal insufficiency. Tenofovir treatment was discontinued. The patient was prescribed 25-OH vitamin D3 4000 IU (100 μg) and oral neutral sodium-potassium phosphate (containing 2000 mg of phosphorus) daily. The pain decreased dramatically after 2 weeks of this treatment. After 8 weeks of treatment, the patient had recovered completely and no longer required painkillers. Laboratory test values returned to normal levels 12 weeks later, with normal bone scintigraphy results.

Figure 1
Figure 1
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DISCUSSION

This patient presented tenofovir-induced acute renal failure and tubular dysfunction, revealed by bone complications. Fanconi syndrome is a tubular dysfunction with several etiologies.5 Severe proximal tubular dysfunction is characterized by glycosuria, aminoaciduria, and excess urinary excretion of phosphate, calcium, bicarbonate, potassium, sodium, and magnesium. Left untreated, hypophosphatemia results in skeletal abnormalities such as rickets in children and osteomalacia in adults.

In our case, kidney function improved and bone abnormalities resolved over several weeks after the cessation of tenofovir treatment, with no change in the other treatments administered. With the exception of NSAIDs prescribed for pain, the patient was not taking any other known nephrotoxic agent.

Tenofovir disoproxil fumarate (Viread) is an adenine analogue reverse transcription inhibitor, prescribed in combination with other antiretroviral treatments for the treatment of HIV-1-infected patients not responding to other drugs. This prodrug is hydrolyzed to produce tenofovir, which has a low bioavailability, at around 25%. It belongs to the same class of drugs as adefovir and cidofovir, which have nephrotoxic effects on the proximal tubules.6 The renal effects of these 2 drugs have been described in detail. They are dose-dependent and related to renal proximal tubule cell dysfunction. They characteristically include high serum creatinine levels, with proteinuria and glycosuria, and low serum potassium, phosphate, uric acid, and bicarbonate levels. Tenofovir is much less nephrotoxic, but a literature review revealed the existence of more than 30 reported cases of tenofovir-associated Fanconi syndrome (Table 1).2–4,7–19 The time between the initiation of tenofovir treatment and the detection of renal abnormalities varied from 1 to 26 months. Most of these patients were also taking other antiretroviral drugs, including ritonavir, which may affect the renal transport of organic anions.20 Hence, as in our patient, treatment with a combination of ritonavir/lopinavir and tenofovir may have increased the intracellular accumulation of tenofovir in the proximal tubules.21 Other interactions may also lead to renal dysfunction.20 The concomitant administration of didanosine is not recommended, for example. NSAIDs22 and a low BMI may increase the bioavailability of tenofovir, thereby also increasing its toxicity. In half the cases identified, serum creatinine concentration returned to baseline values after the treatment was stopped. This tubular toxicity involves accumulation of the drug in cells, after enhanced uptake through human organic anion transporters (located on the basolateral side of the tubule) and a decrease in efflux into the tubular lumen (mediated by multidrug-resistance protein-2).

Table 1
Table 1
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In conclusion, tenofovir, an antiretroviral agent increasingly used to treat HIV-infected patients, displays tubular toxicity that may be revealed by bone complications. Several factors may increase the toxicity of this drug: low BMI (18 kg/m2 in the case presented here), concomitant use of NSAIDs, and prescription of this drug together with other antiretroviral drugs such as ritonavir. The prognosis is usually good, with the effects of renal toxicity generally reversed by treatment discontinuation. Regular renal screening is recommended for patients on tenofovir treatment, to facilitate the detection of tubulopathy. Bone scintigraphy should be carried out in cases of limb pain, before the occurrence of more severe bone complications. Early diagnosis is important, as the disorder can be partly or completely resolved by discontinuing tenofovir treatment.

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REFERENCES

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18. Torres Isidro MV, Garcia Benayas T, del Val Gomez Martinez M, et al. Role of bone gammagraphy in the diagnosis of secondary osteomalacia in a patient treated with tenofovir. Rev Esp Med Nucl. 2006;25:103–106.

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20. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006;42:283–290.

21. Kearney BP, Mathias A, Mittan A, et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr. 2006;43:278–283.

22. Tenofovir and NSAIDs: acute renal failure. Canadian Adverse Reaction Newsletter 2006, 16(2):1. Available at: www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v16n2_e.html.

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Keywords:

tenofovir; human immunodeficiency virus; tubular nephropathy

© 2009 Lippincott Williams & Wilkins, Inc.

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