Tenofovir disoproxil fumarate-induced Fanconi's syndrome during HIV postexposure prophylaxis.

Although the generally good safety profile of tenofovir disoproxil fumarate (TDF) in HIV-infected patients has been demonstrated in most controlled trials and systematic reviews [1–5], a few case reports alert to its potential for significant nephrotoxicity [6–10]. Two cases of Fanconi's syndrome have also recently been reported in hepatitis B monoinfected patients receiving TDF monotherapy [11]. Yet, there is a paucity of data linking TDF-containing regimen to acute renal failure in HIV-negative patients receiving postexposure HIV prophylaxis (PEP) because no tubular dysfunction has yet been reported in this setting [12]. Interestingly, two trials [13] and one prospective study [14] evaluating the tolerability of TDF-containing PEP and including renal function monitoring have not reported any creatinine elevation. We herein report a case of severe tubular dysfunction, which occurred during postexposure HIV prophylaxis in a patient with no previously identified risk for kidney impairment. A 47-year-old White patient was referred to the infectious disease clinic for PEP after a condomless receptive anal intercourse with a casual male encounter of unknown HIV status. The patient denied tobacco and drug consumption, and drank alcohol only on rare occasions. His medical history was limited to 10 years of fenofibrate intake for dyslipidemia and a single episode of kidney lithiasis, successfully treated by extracorporeal lithotripsy 8 years earlier. He occasionally took aspirin for headaches, although not recently, and did not take nonsteroidal anti-inflammatory drugs. No allergy and no relevant familial medical history were identified. His BMI was normal 22.6 kg/m2. According to European AIDS Clinical Society guidelines [15], PEP combining TDF, emtricitabine, darunavir and ritonavir once daily has been prescribed for 28 days. At the baseline visit, HIV and hepatitis C serologic tests were negative, anti-hepatitis B surface antibodies were detected and liver enzymes were normal with a plasma creatinine level of 88 μmol/l – estimated glomerular filtration rate (eGFR) assessed by modification of diet in renal disease formula of 86 ml/min/1.73 m2. Twelve days later, the patient came back to the clinic with his blood test results as scheduled. The clinical tolerability of the treatment was excellent, but the plasma creatinine level had increased to 132 μmol/l (eGFR 54 ml/min/1.73 m2) without any concomitant nephrotoxic drug being used. As the patient had spent the previous days with his father in the south of France, dehydration was suspected despite the absence of diarrhoea and vomiting; the patient was instructed to increase his water intake and to check his plasma creatinine. Four days later, plasma creatinine reached 246 μmol/l (eGFR 26 ml/min/1.73 m2) and PEP was stopped. Renal dysfunction worsened, leading 3 days later to metabolic acidosis and immediate hospitalization in the nephrology ward. Plasma creatinine rose to 444 μmol/l (eGFR 13 ml/min/1.73 m2) and serum bicarbonate decreased to 15 mmol/l. When the patient was admitted to the hospital, he was vomiting and extremely tired with no fever and his blood pressure was stable at 150/80 mmHg. Urinary sediment showed neither white nor red cells and no bacteria, whereas biochemical analysis revealed significant proteinuria (urinary protein/creatinine ration of 284 mg/mmol) mainly of low molecular weight, glycosuria (12 g/l), and hypophosphatemia (0.7 mmol/l). A renal ultrasound excluded pyelocalicial dilatation. A renal biopsy was performed and showed a severe proximal tubular injury with epithelial necrosis, cytoplasmic swelling, vacuolation, and nuclear dystrophy (Fig. 1). Many apoptotic bodies sometimes mixed with irregular size cell debris were also noted in tubular lumens. Interstitium appeared slightly fibroedematous with focal inflammation containing mononuclear elements. By contrast, there was no glomerular or vascular abnormality.FIGURE 1: Severe proximal tubulopathy.This acute kidney injury associated with Fanconi's syndrome was managed with symptomatic treatment – rehydration, alcalinization, antihypertensive support, gastric protection and hypokalema correction. Ten days later, plasma creatinine decreased to 340 μmol/l (eGFR 18 ml/min/1.73 m2). The patient was discharged home with clinical and biological monitoring. Renal function continued to improve with plasma creatinine levels at 170 μmol/l 2 weeks after discharge (eGFR 40 ml/min/1.73 m2), 124 μmol/l 3 weeks later (eGFR 58 ml/min/1.73 m2) and 115 μmol/l 5 months after PEP discontinuation (eGFR 63 ml/min/1.73 m2). Meanwhile, the patient was tested negative for HIV, hepatitis C, chlamydia, gonorrhoea and syphilis. The case report shows that severe tubular toxicity may also occur rapidly in previously healthy individuals receiving TDF with a boosted protease inhibitor (PI), which may increase TDF toxicity [16]. This observation emphasizes the need of renal monitoring before treatment initiation and early after [17]. The use of boosted PI with TDF could be reconsidered and alternatives such as tenofovir alafenamide might be an option for future PEP regimen [18]. Acknowledgements Author's contribution: P.P. took care of the patient and wrote the first draft of the manuscript. C.G. was in charge of the patient in the nephrology ward and for the follow-up. J.V. analysed the kidney biopsy and is the author of the picture (Fig. 1). All authors reviewed and approved the final manuscript. Conflicts of interest There are no conflicts of interest.