Proteinuria Burden and Clinical Outcomes in Patients with Diabetes: A Nationwide Cohort Study

Background: Proteinuria is a well-known risk factor for ESKD, cardiovascular disease (CVD), and all-cause mortality in patients with diabetes mellitus (DM). However, clinical implications of fluctuating proteinuria are poorly understood. We aimed to investigate the association between proteinuria burden outcomes using the Korean National Health Insurance Service data. Methods: This retrospective cohort study included all patients with DM who participated in national health screening between 2015 and 2016 and three health screenings before. Proteinuria burden was defined as the cumulative number of positive dipstick urine protein at each health screening. Outcomes are end-stage kidney disease (ESKD), cardiovascular disease (CVD), and all-cause mortality. Hazard ratio (HR) with 95% confidence interval (CI) were analyzed using Cox proportional hazards regression analysis. Results: Among total 1,262,194 patients, 1,089,833 (86.3%), 118,835 (9.4%), 31,468 (2.5%), 14,827 (1.2%), and 7,231 (0.6%) had proteinuria burden 0, 1, 2, 3, and 4, respectively. There were dose-dependent association between the proteinuria burden and risk of ESKD, CVD, and all-cause mortality (Compared to proteinuria burden 0, adjusted HR [95% CI] for proteinuria burden 1, 2, 3, and 4, respectively: for ESKD, 3.723 [3.421–3.051], 9.565 [8.810–10.384], 15.079 [13.879–16.383], and 20.009 [13.238–21.845]; for CVD, 1.257 [1.214–1.301], 1.578 [ 1.491–1.671], 1.969 [1.832–2.117], and 2.221 [2.023–2.437]; for all-cause mortality: 1.364 [1.320–1.410], 1.653 [1.565–1.745], 2.069 [1.932–2.216], and 2.206 [2.016–2.414]). Early positive proteinuria was worse outcomes than late positive proteinuria within same proteinuria burden. Conclusion: Our study demonstrated that proteinuria burden was dose-dependently associated with ESKD, CVD, and all-cause mortality in patients with DM. Patients with DM who have even a single positive dipstick test require active management.