[NATAP] Tenofovir Renal Effects

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Progression of renal impairment under therapy with tenofovir

AIDS: Volume 19(12) 12 August 2005 p 1332-1333

Letter To The Editor

Jülg, Boris Dominika; Bogner, Johannes a; Crispin, b; Goebel, -Detlefa

aDepartment of Infectious Diseases, Medizinische Poliklinik

bDepartment of Medical Informatics, Biometry, and Epidemiology, Ludwig Maximilian University, Munich, Germany.

Ed Note: risk factors include glucose impairment.

Mauss et al. [1] recently reported a reduction in the glomerular filtration rate (GFR) in HIV patients treated with tenofovir in a cross-sectional study. We wish to communicate our data on GFR reduction in a longitudinal analysis over 12 months of treatment with tenofovir.

Tenofovir disoproxil fumarate, an acyclic nucleotide analogue of adenosine monophosphate, belongs to the family of nucleotide reverse transcriptase inhibitors that includes cidofovir and adefovir. Both cidofovir and adefovir have well-documented renal toxicities, including proximal renal dysfunction and acute renal failure [2,3]. Although some studies have documented efficacy and safety, suggesting that tenofovir disoproxil fumarate is not associated with severe nephrotoxicity [4,5], a number of different manifestations of kidney disease have been described with tenofovir, including Fanconi-like syndrome, diabetes insipidus, and acute renal failure [6].

To investigate the impact of tenofovir on renal function over a period of 12 months, we retrospectively collected data on the serum-creatinine levels of 52 patients being treated with tenofovir and compared them with patients on antiretroviral therapy never treated with tenofovir (n = 56). Values for serum creatinine were collected 2 and 1 month before and after starting treatment at month 1, 3, and 12. From these data we calculated the estimated GFR using the modification of diet in renal disease (MDRD) equation incorporating age, race, sex, and serum creatinine levels: estimated GFR = 186.3 × (serum creatinine level [in milligrams per decilitre])-1.154 × (age [in years])-0.203 × 0.742 if female × 1.21 if black [7].

Compared with the mean GFR (mean ± standard deviation: 101.36 ± 21.13 ml/min per 1.73 m2) before the tenofovir treatment was started, patients on tenofovir showed a lower mean GFR estimated by the MDRD formula at month 1 (97.79 ± 21.60 ml/min per 1.73 m2), month 3 (97.59 ± 20.52 ml/min per 1.73 m2), and month 12 (94.48 ± 19.97 ml/min per 1.73 m2).

Controls, i.e. patients on tenofovir-free antiretroviral therapy, showed a slight decrease in their estimated GFR over the period of one year. Compared with the baseline GFR (101.47 ± 20.59 ml/min per 1.73 m2), GFR values at month 1 (101.48 ± 20.80 ml/min per 1.73 m2), month 2 (102.12 ± 20.24 ml/min per 1.73 m2), and month 12 (100.60 ± 20.03 ml/min per 1.73 m2) changed marginally (see Fig. 1).

These results suggest that treatment with tenofovir is associated with a progressive time-dependent loss in mean GFR, as estimated by the MDRD equation. Altogether, after 12 months of observation the mean GFR in the tenofovir-treated group dropped to 94.48 ml/min per 1.73 m2, which means a loss of -7.48 ml/min per 1.73 m2 [95% confidence interval (CI) -11.35 to -3.60]. In the control group on antiretroviral therapy without tenofovir, the mean GFR showed a difference of -0.87 ml/min per 1.73 m2 (95% CI -5.67 to +3.94). At month 12, the difference between the GFR decreases in the tenofovir and the control group were significant (t105 = 2.12; P = 0.036). It has to be added, however, that the mean GFR was still within the normal range in both groups (> 90 ml/min per 1.73 m2).

In conclusion, mild renal dysfunction in patients treated with tenofovir as published before should be taken into consideration in the design of future trials. In particular, the continuous loss in the mean GFR under tenofovir suggests an increasing renal dysfunction caused for example by the accumulation of tenofovir disoproxil fumarate in the tubular system. Future investigations should include time on treatment and the reversibility of GFR impairment.

References

1. Mauss S, Berger F, Schmutz G. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS 2005; 19:93-95.

2. Meier P, Dautheville-Guibal S, Ronco PM, Rossert J. Cidofovir induced end-stage renal failure. Nephrol Dial Transplant 2002; 17:148-149.

3. Tanji N, Tanji K, Kambham N. Adefovir nephrotoxicity possible role for mitochondrial DNA depletion. Hum Pathol 2001; 32:734-740.

4. Schooley RT, Ruane P, Myers RA, Beall G, Lampris H, Berger D, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16:1257-1263.

5. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, M, et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001; 45:2733-2739.

6. Karras A, Lafauri M, Furco A, Bourgarit A, Droz D, Sereni D, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus infected patients three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003; 36:1070-1073.

7. Levey AS, Bosch JP, JB, Greene T, Rodgers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130:461-470.