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-beta-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 mu g/g [range, 26.8-17,454.5 mu g/g]) than in the ART-naive group (92.5 mu g/g [range, 21.3-3,969.0 mu g/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 mu g/g [range, 31.0-6,136.3 mu g/g]; P = 0.08). U(NAG/C) excretion was significantly higher in both the TDF (median, 394.7 mu mol/h/g [range, 140.5-10,851.3 mu mol/h/g]; P = 0.01) and non-TDF (406.8 mu mol/h/g [range, 12.4-8,485.8 mu mol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 mu mol/h/g [range, 56.5-2,876.1 mu mol/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. Am J Kidney Dis 54:1034-1042. (C) 2009 by the National Kidney Foundation, Inc.