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.


METHODS
Cross-sectional.


METHODS
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.


METHODS
Exposure to TDF.


RESULTS
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 microg/g [range, 26.8-17,454.5 microg/g]) than in the ART-naive group (92.5 microg/g [range, 21.3-3,969.0 microg/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 microg/g [range, 31.0-6,136.3 microg/g]; P = 0.08). U(NAG/C) excretion was significantly higher in both the TDF (median, 394.7 micromol/h/g [range, 140.5-10,851.3 micromol/h/g]; P = 0.01) and non-TDF (406.8 micromol/h/g [range, 12.4-8,485.8 micromol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 micromol/h/g [range, 56.5-2,876.1 micromol/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.


CONCLUSIONS
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.
Hall
Andrew M
AM
Department of Cell and Developmental Biology, University College of London, London, UK. andrew.hall@ucl.ac.uk
Edwards
Simon G
SG
Lapsley
Marta
M
Connolly
John O
JO
Chetty
Kreesan
K
O'Farrell
Stephen
S
Unwin
Robert J
RJ
Williams
Ian G
IG
D000118:Acetylglucosaminidase / Q000652:urine; D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D044966:Anti-Retroviral Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D003404:Creatinine / Q000652:urine; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000009:adverse effects* / Q000627:therapeutic use*; D010710:Phosphates / Q000097:blood; D011507:Proteinuria / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D012177:Retinol-Binding Proteins / Q000652:urine; D012307:Risk Factors; D012680:Sensitivity and Specificity; D000068698:Tenofovir
D044966:Anti-Retroviral Agents; D063065:Organophosphonates; D010710:Phosphates; D012177:Retinol-Binding Proteins; D000068698:Tenofovir; D003404:Creatinine; D000118:Acetylglucosaminidase; D000225:Adenine