Of the 20 cases reporting complete antiretroviral information (medications and doses), 13 patients received concomitant tenofovir and 17 patients received 100 mg ritonavir. Among 14 cases reporting stone analysis, 12 had atazanavir confirmed by infrared spectrophotometry or other analysis. In six cases with available data, atazanavir concentrations in the stone ranged from 40 to 100%. In 17 cases with complete atazanavir treatment history, the median time between atazanavir initiation and the onset of nephrolithiasis was 1.7 years (range 5 weeks to 6 years).
Among the 30 patients, 18 required hospitalization, seven received outpatient care, and five lacked data. Interventions for stone removal were performed in eight patients (27%). Two patients required lithotripsy only, one patient underwent both lithotripsy and ureteral stent insertion, one patient needed nephrostomy tube placement for the relief of severe hydronephrosis because of ureteral obstruction by the calculus, two patients had ureteral stent insertion and endoscopic surgical extraction of the stone, and two patients needed endoscopic surgical extraction of the stone. In addition to clinical symptoms associated with nephrolithiasis, some patients also reported concurrent laboratory and radiological abnormalities [4,5]. Five patients developed renal insufficiency (four with acute renal insufficiency and one with a worsening of baseline chronic renal insufficiency) at the time of nephrolithiasis. In all four cases of acute renal insufficiency, renal function returned to baseline after stone removal and atazanavir discontinuation. In the patient who developed a worsening of baseline chronic renal insufficiency, renal function improved but had not returned to its previous baseline after stone removal. Three patients had radiological documentation of hydronephrosis. Of the 30 cases, atazanavir was reported as discontinued in nine cases (30%) after nephrolithiasis was diagnosed.
Data submitted to a voluntary reporting system such as the AERS are often limited by the absence of detailed and pertinent information, such as demographics, weight (only available for seven patients in the study), medical co-morbidities (particularly conditions that predispose to nephrolithiasis [4,5]), duration of atazanavir exposure, continuation of atazanavir after nephrolithiasis was diagnosed (only available for 15 patients), atazanavir drug levels (only available for one patient ), doses of any concurrent medications, diagnostic evaluation, patient management, and clinical outcome. As these adverse drug events are obtained voluntarily from a population of unknown size, the ability to make reliable estimates in frequency or establish a causal relationship with drug exposure is not always possible. Despite these limitations, our study findings from the AERS database suggest that atazanavir can be associated with nephrolithiasis. In the AERS database, 30 cases were identified, of which 12 cases had confirmed atazanavir by infrared spectrophotometry or other analysis. Only two of the confirmed cases (patients 18 and 23) have been reported in the literature [1,2]. In addition to the 12 confirmed atazanavir-associated cases, five cases were excluded that could have been confirmed as atazanavir-associated cases with better follow-up information. Three patients had reports that stated ‘kidney stones observed through lab work’, but provided no details regarding the composition of the stones (patients 8, 9, and 10). Furthermore, two patients had stone analysis but incomplete characterization of the stone metabolite (patient 25) or possible inaccurate reporting of the data (patient 30). It is conceivable that, with better follow-up information, some or all of these five cases could also be confirmed as being associated with the use of atazanavir.
The mechanism for the development of atazanavir-associated nephrolithiasis is unknown. Further information is needed to determine whether patients with pre-existing hepatic or renal impairment or a history of nephrolithiasis are at an increased risk of this event. Data are not currently available to determine whether increased atazanavir exposures or prolonged atazanavir use is associated with these events.
Nephrolithiasis associated with atazanavir can cause significant morbidity, including renal dysfunction and hydronephrosis. Many cases required hospitalization for management and symptom relief. Lithotripsy, ureteral stent insertion, nephrostomy tube placement, or endoscopic stone removal was needed in a subset of cases. Some cases of nephrolithiasis resulted in the discontinuation of atazanavir. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with the use of atazanavir. If signs or symptoms of nephrolithiasis occur, healthcare providers should consider temporary interruption or discontinuation of atazanavir therapy.
Conflicts of interest: None.
1. Pacanowski J, Poirier JM, Petit I, Meynard JL, Girard PM. Atazanavir urinary stones in an HIV-infected patient. AIDS 2006; 20:2131.
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3. Kessler DA. Introducing MEDWatch. A new approach to reporting medication and device adverse effects and product problems. JAMA 1993; 269:2765–2768.
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© 2007 Lippincott Williams & Wilkins, Inc.
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