Key Points Among adults with diabetes and CKD, biomarkers of kidney tubule health were associated with a greater risk of death, independent of eGFR, albuminuria, and additional risk factors.Higher urine levels of YKL-40 and KIM-1 were associated with a greater risk of death. For cause-specific death, UMOD was independently and inversely associated with the risk of cardiovascular death. Background Kidney disease assessed by serum creatinine and albuminuria are strongly associated with mortality in diabetes. These markers primarily reflect glomerular function and injury. Urine biomarkers of kidney tubule health were recently associated with the risk of kidney failure in persons with CKD and diabetes. Associations of these biomarkers with risk of death are poorly understood. Methods In 560 persons with diabetes and eGFR ≤60 ml/min per 1.73 m² from the Reasons for Geographic and Racial Differences in Stroke study (47% male, 53% Black), we measured urine biomarkers of kidney tubule health at baseline: monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin, kidney injury molecule-1 (KIM-1), EGF, chitinase-3-like protein 1 (YKL-40), and uromodulin (UMOD). Cox proportional hazards regression was used to examine the associations of urine biomarkers with all-cause and cause-specific mortality in nested models adjusted for urine creatinine, demographics, mortality risk factors, eGFR, and urine albumin. Results The mean (SD) age was 70 (9.6) years, and baseline eGFR was 40 (3) ml/min per 1.73 m². There were 310 deaths over a mean follow-up of 6.5 (3.2) years. In fully adjusted models, each two-fold higher urine concentration of KIM-1 and YKL-40 were associated with all-cause mortality (hazard ratio [HR] 1.15, 95% confidence interval [CI], 1.01 to 1.31 and 1.13, 95% CI, 1.07 to 1.20, respectively). When examining cause-specific mortality, higher UMOD was associated with a lower risk of cardiovascular death (adjusted HR per two-fold higher concentration 0.87, 95% CI, 0.77 to 0.99), and higher MCP-1 was associated with higher risk of cancer death (HR per two-fold higher concentration 1.52, 95% CI, 1.05 to 2.18). Conclusion Among persons with diabetes and CKD, higher urine KIM-1 and YKL-40 were associated with a higher risk of all-cause mortality independently of established risk factors. Urine UMOD and MCP-1 were associated with cardiovascular and cancer-related death, respectively.