Subclinical Tubular Injury in HIV-Infected Individuals on Antiretroviral Therapy: A Cross-sectional Analysis

Background

Randomized control studies have not shown an association between treatment with tenofovir (TDF) and clinically significant kidney toxicity. However, multiple cases of renal tubular toxicity have been described in patients with HIV treated with TDF. It is unclear whether spot urine protein- or albumin-creatinine ratio is a sufficiently sensitive screening test to detect subclinical renal tubular toxicity in patients with HIV.

Study Design

Cross-sectional.

Setting & Participants

99 patients with HIV with serum creatinine levels < 1.70 mg/dL and dipstick-negative proteinuria; 19 were antiretroviral treatment (ART) naive, 47 were on a TDF regimen, and 33 were on ART, but with no history of TDF exposure.

Predictor or Factor

Exposure to TDF.

Outcomes

Spot urine concentrations of retinol-binding protein (RBP; a low-molecular-weight protein normally reabsorbed by the proximal tubule), N-acetyl-β-d-glucosaminidase (NAG; a proximal tubule lysosomal enzyme), albumin (A; a marker of glomerular disease), and protein (P; a standard clinical screening test for kidney pathological states) expressed as a ratio to creatinine (C; U_RBP/C, U_NAG/C, U_A/C, and U_P/C, respectively).

Results

There were no significant differences in median U_A/C (ART-naive, 7.3 mg/g [range, 0-245.8 mg/g]; TDF, 9.0 mg/g [range, 0.1-184.1 mg/g]; and non-TDF, 10.5 mg/g [range, 2.6-261.6 mg/g]; P = 0.8). U_RBP/C excretion was significantly higher in the TDF group (median, 214.2 μg/g [range, 26.8-17,454.5 μg/g]) than in the ART-naive group (92.5 μg/g [range, 21.3-3,969.0 μg/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 μg/g [range, 31.0-6,136.3 μg/g]; P = 0.08). U_NAG/C excretion was significantly higher in both the TDF (median, 394.7 μmol/h/g [range, 140.5-10,851.3 μmol/h/g]; P = 0.01) and non-TDF (406.8 μmol/h/g [range, 12.4-8,485.8 μmol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 μmol/h/g [range, 56.5-2,876.1 μmol/h/g]). U_P/C was significantly higher in the TDF (median, 123.9 mg/g [range, 53.1-566.4 mg/g]) than the non-TDF group (97.3 mg/g [range, 0-451.3 mg/g]; P = 0.03). The proportion of patients with evidence of tubular dysfunction (increased U_RBP/C and/or U_NAG/C) was considerably higher than the proportion with an increase in U_A/C or U_P/C in all groups: for ART-naive, 52.6% vs 31.6% vs 25.0%; for TDF, 80.9% vs 29.8% vs 52.2%; and for non-TDF, 81.8% vs 39.4% vs 30.0%. The level of agreement among the different urinary test results was low.

Limitations

Causality cannot be established from single measurements of urinary markers in a cross-sectional study.

Conclusions

Patients with HIV had high rates of subclinical proteinuria, but neither U_P/C nor U_A/C is sufficiently sensitive alone to detect many of these cases. Patients using TDF have increased U_RBP/C and U_P/C; the significance of this will need to be determined from longer-term outcome studies.

Index Words: HIV, renal tubule, antiretroviral therapy, tenofovir, proteinuria