Urine Proteomic Signatures of Kidney Function Decline after Hospitalization

Urine proteomics may provide mechanistic insights on why patients experience a higher risk of kidney function decline after hospitalization. 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 urine proteins collected at 3 months post-hospitalization and determined their association with estimated glomerular filtration rate (eGFR) decline during median [IQR] of 5.1[4.0-6.0] years follow-up. In four independent cohorts including the Kidney Precision Medicine Project (KPMP), we determined if 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. 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. Urinary proteins reflecting degenerative tubular injury, inflammation, and fibrosis are associated with eGFR decline in recently hospitalized patients. The Kidney Precision Medicine Project (KPMP) is supported by the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) through the following grantsU01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937 We gratefully acknowledge the essential contributions of our patient participants and support of the American public though their tax dollars. SM is supported by NIDDK Grant K23DK128358.