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Kidney Renal Markers Signal Linked to Higher Tenofovir Plasma Levels
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Higher tenofovir plasma concentrations correlated with kidney tubular dysfunction (KTD), a signal of kidney problems associated with tenofovir disoproxil fumarate (TDF, Viread), in a 161-person study [1]. Results of this cross-sectional analysis, conducted by David Burger and his Nijmegen group, are all the more intriguing because a 10-day monotherapy trial presented at this conference found greater HIV RNA suppression with 40 mg of a tenofovir prodrug (and 79% lower plasma levels) than with the standard 300 mg of TDF [2].
Asymptomatic KTD is often the first sign of renal dysfunction, Burger and colleagues noted. Older age, use of protease inhibitors, and low weight have been linked to KTD in people taking TDF. Reasoning that all these risk factors may be proxies for increased tenofovir plasma concentrations, Burger set out to assess the relation between KTD and tenofovir levels in HIV-positive people taking TDF for at least 1 year.
The investigators measured mid-dose (12-hour) tenofovir concentrations in plasma, as well as creatinine, glucose, phosphate, and uric acid. They collected urine to measure alpha1-microglobulin, creatinine, glucose, phosphate, and uric acid. The researchers defined KTD as presence of at least two of four markers:
-- Urinary alpha1-microglobulin/creatinine ratio > 15 mg/10 mmol
-- Fractional excretion of phosphate > 20% and hypophosphatemia
-- Functional excretion of uric acid > 10% and decreased plasma uric acid levels
-- Glucosuria (urinary glucose > 1.7 mmol/L with plasma glucose < 10 mmol/L)
The Nijmegen team found 161 people taking TDF for at least a year, 101 (63%) of whom had at least one marker of KTD and 17 (10.6%) of whom met the definition of KTD. The 17 patients with KTD had significantly higher plasma creatinine (88.5 versus 78.4 umol/L, P = 0.008) and a significantly lower MDRD-determined glomerular filtration rate (80.9 versus 92.6 mL/min/1.73m2, P = 0.01).
The KTD group had taken TDF longer than those without KTD (average 46.3 versus 39.1 months), but that difference lacked statistical significance (P = 0.16). The groups did not differ from each other in gender, weight, antiretroviral duration, protease inhibitor use, detectable viral load, CD4 count, or prevalence of hypertension, diabetes, hepatitis B surface antigen positivity, hepatitis C antibody positivity, or nephrotoxic medication use.
Plasma tenofovir concentration was significantly higher in people with KTD than in those without KTD (0.143 versus 0.108 mg/L, P = 0.04). The group with KTD also had a significantly higher alpha1-microglobulin/creatinine ratio (77.4 versus 25.7 mg/10 mmol, P < 0.001), significantly higher functional excretion of phosphate (19.9% versus 12.0%, P < 0.001), significantly higher functional excretion of uric acid (11.8% versus 6.8%, P = 0.002), and significantly higher glucosuria (2% versus 0, P = 0.011).
Multivariate logistic regression identified tenofovir plasma concentration as the only variable independently associated with KTD. (The investigators did not spell out details of that analysis in their poster.)
Post hoc analysis found a stronger association between KTD and the product of tenofovir plasma concentrations and tenofovir exposure. The investigators proposed that association could suggest cumulative toxicity.
Burger and colleagues called for longitudinal research "to investigate the development and clinical relevance of the observed KTD."
References
1. Ezinga M, Wetzels J, Van der Ven A, Burger D. Kidney tubular dysfunction is related to tenofovir disoproxil fumarate plasma concentration. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 603.
2. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103.
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