Abstract
BACKGROUND. Urine proteomics may provide mechanistic insights on why patients experience a higher risk of kidney function decline after hospitalization. METHODS. In 174 patients with and without acute kidney injury (AKI) from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI) cohort, we used Olink to profile 2783 urinary proteins collected at 3 months after hospitalization and determined their association with estimated glomerular filtration rate (eGFR) decline during median [IQR] of 5.1 [4.0 to 6.0] years follow-up. In 4 independent cohorts, including the Kidney Precision Medicine Project (KPMP), we determined whether proteins were differentially expressed with AKI. We used weighted correlation network analysis to determine proteins’ cellular enrichment in the kidney transcriptome (single-cell and spatial transcriptomics) in patients with AKI receiving research kidney biopsy.RESULTS. We identified 387 and 10 proteins associated with faster and slower eGFR decline, respectively, most of which were differentially expressed in patients at the time of AKI. Among these proteins, 283 (71%) were expressed by kidney cells in participants with AKI from KPMP. The expression formed 3 clusters enriched in the proximal tubule, degenerative tubule and myeloid cells, and stromal cells, and correlated with histopathological features of AKI, such as tubular injury, interstitial inflammation, and fibrosis, respectively.CONCLUSION. Urinary proteins reflecting degenerative tubular injury, inflammation, and fibrosis are associated with eGFR decline in recently hospitalized patients.FUNDING. National Institute of Diabetes and Digestive Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, UH3DK114937, K23DK128358, R01DK128087, and R01DK140717.
Authors
Yumeng Wen, Steven Menez, Heather Thiessen Philbrook, Dennis Moledina, Steven G. Coca, Jiashu Xue, James Kaufman, Vernon Chinchillil, Paul L. Kimmel, T. Alp Ikizler, Chi-Yuan Hsu, Tanika Kelly, Ana Ricardo, Jonathan Himmelfarb, Chirag R. Parikh, ASSESS-AKI, TRIBE-AKI, and Kidney Precision Medicine Project consortia
Figure 4
Urinary proteins associated with longitudinal eGFR decline are associated with distinct histopathological features of kidney disease in patients with AKI.
