Vasantha Jotwani1,2, Pranav S Garimella3,4, Ronit Katz5, Rakesh Malhotra3,4, Jeffrey Bates6, Alfred K Cheung7, Michel Chonchol8, Paul E Drawz9, Barry I Freedman10, William E Haley11, Anthony A Killeen12, Henry Punzi13, Mark J Sarnak14, Mark S Segal15, Michael G Shlipak16,17, Joachim H Ix3,4. 1. Department of Medicine, San Francisco VA Medical Health Care System, San Francisco, California, USA, vasantha.jotwani@ucsf.edu. 2. Kidney Health Research Collaborative, San Francisco VA Medical Center and University of California, San Francisco, California, USA, vasantha.jotwani@ucsf.edu. 3. Department of Medicine, University of California, San Diego, California, USA. 4. Veterans Affairs San Diego Healthcare System, San Diego, California, USA. 5. Kidney Research Institute, University of Washington, Seattle, Washington, USA. 6. Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA. 7. Department of Medicine, University of Utah, Salt Lake City, Utah, USA. 8. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. 9. Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. 10. Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 11. Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA. 12. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. 13. Punzi Medical Center, Trinity Hypertension Research Institute, Carollton, Texas, USA. 14. Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA. 15. Department of Medicine, University of Florida, Gainesville, Florida, USA. 16. Department of Medicine, San Francisco VA Medical Health Care System, San Francisco, California, USA. 17. Kidney Health Research Collaborative, San Francisco VA Medical Center and University of California, San Francisco, California, USA.
Abstract
BACKGROUND: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD. METHODS: We measured baseline urine concentrations of uromodulin, β2-microglobulin (β2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR <60 mL/min/1.73 m2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm. RESULTS: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary β2m was associated with faster % annual eGFR decline (-0.10 [95% CI: -0.18, -0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [-0.13, 0.35], p value for interaction by treatment arm = 0.045) or β2m (-0.01 [-0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [-0.22, 0.23]) or intensive (0.03 [-0.20, 0.25]) arm. CONCLUSIONS: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.
BACKGROUND: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD. METHODS: We measured baseline urine concentrations of uromodulin, β2-microglobulin (β2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR <60 mL/min/1.73 m2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm. RESULTS: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary β2m was associated with faster % annual eGFR decline (-0.10 [95% CI: -0.18, -0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [-0.13, 0.35], p value for interaction by treatment arm = 0.045) or β2m (-0.01 [-0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [-0.22, 0.23]) or intensive (0.03 [-0.20, 0.25]) arm. CONCLUSIONS: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.
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