Association of Urinary Biomarkers of Kidney Injury with Estimated GFR Decline in HIV-Infected Individuals following Tenofovir Disoproxil Fumarate Initiation

Clin J Am Soc Nephrol. 2018 Sep 7;13(9):1321-1329. doi: 10.2215/CJN.01700218. Epub 2018 Aug 28.


Background and objectives: Tenofovir disoproxil fumarate (tenofovir) is associated with elevated concentrations of biomarkers of kidney damage and dysfunction in individuals with HIV. The relationship of these kidney biomarkers with longitudinal kidney function decline is unknown.

Design, setting, participants, & measurements: We evaluated associations of 14 urinary biomarkers of kidney injury with changes in eGFR among 198 men and women with HIV who initiated tenofovir between 2009 and 2015 in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Urinary biomarkers included albumin-to-creatinine ratio, α-1-microglobulin, β-2-microglobulin, cystatin C, kidney injury molecule-1 (KIM-1), IL-18, neutrophil gelatinase-associated lipocalin (NGAL), clusterin, osteopontin, uromodulin, monocyte chemoattractant protein-1, EGF, trefoil factor 3, and chitinase 3-like protein 1. We used multivariable linear mixed-effect models controlling for demographics, traditional kidney disease risk factors, and HIV-related risk factors to evaluate associations of baseline biomarkers with first-year changes in eGFR, and associations of year 1 and first-year change in biomarkers with changes in eGFR from year 1 to year 3. We used the least absolute shrinkage and selection operator method to identify a parsimonious set of biomarkers jointly associated with changes in eGFR.

Results: Median eGFR before tenofovir initiation was 103 (interquartile range, 88-116) ml/min per 1.73 m2. During the first year of tenofovir use, eGFR decreased on average by 9.2 (95% confidence interval, 6.5 to 11.9) ml/min per 1.73 m2 and was stable afterward (decrease of 0.62; 95% confidence interval, -0.85 to 2.1 ml/min per 1.73 m2 per year). After multivariable adjustment, higher baseline β-2-microglobulin, KIM-1, and clusterin were associated with larger first-year eGFR declines, whereas higher baseline uromodulin was associated with a smaller eGFR decline. First-year increase in urinary cystatin C and higher year 1 IL-18 were associated with larger annual eGFR declines from year 1 to year 3. The parsimonious models identified higher pre-tenofovir clusterin and KIM-1, lower pre-tenofovir uromodulin, and higher year 1 IL-18 as jointly associated with larger eGFR declines.

Conclusions: Urinary biomarkers of kidney injury measured before and after tenofovir initiation are associated with subsequent changes in eGFR in individuals with HIV.

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Keywords: Acquired Immunodeficiency Syndrome; Albumins; Biomarkers; Chemokine CCL2; Cohort Studies; Cystatin C; Demography; HIV; Hepatitis A Virus Cellular Receptor 1; Kidney injury; LCN2 protein, human; Lipocalin-2; Tenofovir; Tenofovir disoproxil fumarate; Uromodulin; creatinine; epidermal growth factor; glomerular filtration rate; interleukin 18 protein, human; risk factors.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Webcast

MeSH terms

  • Adult
  • Anti-HIV Agents / adverse effects*
  • Anti-HIV Agents / therapeutic use
  • Biomarkers / urine
  • Female
  • Glomerular Filtration Rate*
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • HIV Infections / physiopathology*
  • HIV Infections / urine
  • Humans
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / physiopathology*
  • Kidney Diseases / urine
  • Male
  • Middle Aged
  • Prospective Studies
  • Tenofovir / adverse effects*
  • Tenofovir / therapeutic use


  • Anti-HIV Agents
  • Biomarkers
  • Tenofovir