Renal tubule damage with tenofovir despite normal glomerular function

Asymptomatic renal tubule damage may affect people taking tenofovir even if they have a normal glomerular filtration rate, according to findings in a prospective Spanish study. [1] Older age and treatment with tenofovir both independently predicted renal tubule dysfunction in these patients.

Madrid clinicians measured 24-hour urine in three unmatched groups: 81 antiretroviral-naîve people with HIV, 49 antiretroviral-treated people who never took tenofovir, and 154 tenofovir-treated individuals. The naïve people were significantly younger than both antiretroviral-experienced groups, but median age was similar in the non-tenofovir-experienced group and the tenofovir group (46 and 44 years). CD4 counts were statistically equivalent in the two experienced groups (572 and 487, p=0.2). Similar proportions in all three groups had hypertension or took nephrotoxic drugs (other than tenofovir), and about 25% of people in the two experienced groups had diabetes.

Creatinine clearance was lower in tenofovir takers (109 mL/min) than in the other groups (119 mL/min in the nontenfovir treated group and 123 mL/min in the untreated group), but not significantly so. Fractional tubular resorption of phosphorus was significantly lower in the tenofovir group than in either of the other groups: 82% versus 87% in naïve patients (p< 0.001) and 85% in non-tenofovir-treated people (p=0.002).

The investigators defined altered tubular function as having two of the three following conditions: nondiabetic glucosuria, reduced tubular resorption of phosphorus, or pathologic aminoaciduria. By that definition, 22% taking tenofovir had tubular damage versus 6% taking a nontenofovir regimen (P = 0.01) and 12% taking no antiretrovirals (P = 0.06). Among people taking tenofovir, 51.4% had fractional tubular resorption of phosphorus (versus 27.1% taking a nontenofovir regimen, P = 0.003); 11.4% had fractional excretion of uric acid (versus 0 taking a nontenofovir regimen, P = 0.01); and 19.5% had beta2 microglobulinuria (versus 4.3% taking a nontenofovir regimen, P = 0.01).

Multivariate analysis determined that a tenofovir-containing regimen independently raised the risk of renal tubule damage more than 20 times (odds ratio 21.6, 95% confidence interval 4.1 to 13, P < 0.001). Every extra year of age raised the risk 6% (odds ratio 1.06, 95% confidence interval 1.0 to 1.1, P = 0.01). Variables that did not affect the risk of tubule damage in this analysis were gender, body weight, history of hypertension or diabetes, viral load, CD4 count, length of antiretroviral therapy, protease inhibitor therapy, concomitant nephrotoxic drugs, or hepatitis B or C virus coinfection. Kaplan-Meier survival analysis confirmed a significantly higher risk of tubule dysfunction with tenofovir than with a non-tenofovir combination (P < 0.001).

The investigators concluded that tenofovir, though “relatively safe,” may be linked to functional damage of the proximal renal tubule. And that damage may be asymptomatic when studied prospectively. They proposed that “the long-term consequences of abnormal tubular dysfunction in patients on tenofovir warrant close examination.”