Acute tubular necrosis in a patient receiving tenofovir.

Abstract

Tenofovir disoproxil fumarate (tenofovir DF), a nucleotide reverse transcriptase inhibitor, was approved by the US Food and Drug Administration in late 2001. Tenofovir DF has shown efficacy as a part of highly active antiretroviral therapy (HAART) in treatment-experienced patients [1], and it has also shown efficacy in treatment-naive HIV-positive patients [2]. The side-effects to tenofovir are mainly mild to moderate gastrointestinal intolerances: nausea, vomiting, diarrhea, and flatulence. This antiretroviral drug is primarily eliminated through the kidneys by glomerular filtration and active tubular secretion [1]. We report a case of acute tubular necrosis suspected in a patient receiving tenofovir DF as a component of his antiretroviral regimen. The patient is a 50-year-old Caucasian man, diagnosed with HIV in 1987, with a past medical history including hypertension, eosinophilic dermatitis, amoebic dysentery, herpes zoster and oral candidiasis. The patient has received various regimens of antiretroviral agents without achieving acceptable viral suppression. When the patient's viral load was 132 355 copies/ml (5.12 log) and his CD4 cell count was 20 cells/ml at 3%, his regimen was subsequently changed from didanosine, saquinavir and ritonavir to stavudine, lamivudine, tenofovir DF and lopinavir–ritonavir based on his past history, intolerances and genotype information. Other medications included sulfamethoxazole–trimethoprim, azithromycin, valacyclovir, fluconazole, quinapril, atenolol and lorazepam. There was no reported history of any non-steroidal anti-inflammatory drug use, toxin exposure, radiocontrast dye, chronic diarrhea or dehydration, except for the episode of amoebic dysentery. When treatment was initiated with the tenofovir DF regimen, the patient's serum creatinine level was 97.2 μmol/l (1.1 mg/dl), with an estimated creatinine clearance of 82 ml/min. Over the next 5 months, the serum creatinine level progressively increased to 176.8 μmol/l (2.0 mg/dl). The patient was referred to a nephrologist, who stopped the quinapril and valacyclovir in June. A renal biopsy performed 6 weeks later revealed severe acute tubular necrosis, with early regeneration evident at this point. There was a mild degree of diffuse interstitial fibrosis with patchy mild tubular atrophy. All medications were dose-adjusted based on renal function except for tenofovir DF. A 24 h urine collection showed a creatinine clearance of 20 ml/min with a serum creatinine level of 450 μmol/l (5.1 mg/dl). This was a progressive increase in the serum creatinine level since stopping quinapril and valacyclovir 3 months earlier. As this was the first time this patient had successfully responded to HAART, he was given the option of dialysis. He decided to stop his HAART. After discontinuing his antiretroviral drugs, his serum creatinine level dropped to 194.4 and 176.8 μmol/l (2.2 and 2.0 mg/dl) at 1 and 2 months, respectively. In tenofovir DF studies, increases in the serum creatinine level were shown as mostly being of grade one severity (≥ 44 μmol/l; ≥ 0.5 mg/dl from baseline), were considered transient and resolved with continued tenofovir DF treatment [3]. In the 903 trial, there was a 1% incidence of grade one and grade two severity [2]. The tenofovir DF expanded access program showed a 0.3% incidence of renal abnormalities [4]. Post-marketing reports of renal adverse events included renal insufficiency, kidney failure, Fanconi syndrome and increased creatinine levels. These occurred in patients with underlying renal disease or who were receiving concomitant nephrotoxic agents [1]. After dose-adjusting all medications for renal function and stopping the quinapril and valacyclovir, there was still a progressive increase in the serum creatinine level. Tenofovir DF was the only medication not dose-adjusted as there was no information from the manufacturer at the time. Lamivudine, stavudine and lopinavir–ritonavir do not indicate renal dysfunction as an adverse effect in their product monographs [5–7]. As the patient had finally achieved virological success on HAART, it was decided to continue therapy and monitor renal function. The patient had received lamivudine, stavudine and lopinavir–ritonavir without any adverse events in the past. There is now new information regarding dosage adjustment studied in healthy volunteers and in HIV patients receiving tenofovir DF, using alternate day dosing, with renal impairment as a result of the inability to split the almond-shaped tablet. There have been other cases of acute tubular necrosis related to tenofovir [8]. The monitoring of serum creatine levels is recommended in older patients with impaired renal function.