Frequency and sequence of proteinuria positivity and clinical outcomes in patients with diabetes: A nationwide cohort study

Proteinuria is a risk factor for end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with diabetes. However, the clinical implications of fluctuating proteinuria are unclear. We investigated the proteinuria burden and the risks of clinical outcomes in patients with diabetes using the Korean National Health Insurance Service database. This retrospective cohort study included patients with diabetes who participated in a national health screening between 2015 and 2016, with records of three previous health screenings. Each end-point was followed until 31 December 2022. The proteinuria burden (range: 0-4) was defined as the cumulative number of positive urine protein dipstick tests at each health screening. The outcomes included ESKD, CVD and all-cause mortality. Among 1 264 699 patients, 86.3%, 9.4%, 2.5%, 1.2% and 0.6% had proteinuria burdens of 0 to 4, respectively. The proteinuria burden and risks of clinical outcomes had dose-dependent associations; compared to proteinuria burden 0, the adjusted hazard ratio (95% confidence interval) of proteinuria burdens 1, 2, 3 and 4, respectively, were as follows: ESKD, 3.539 (3.326-3.766), 9.373 (8.816-9.965), 14.539 (13.652-15.484) and 19.704 (18.412-21.087); CVD, 1.247 (1.214-1.280), 1.530 (1.465-1.599), 1.815 (1.713-1.923) and 2.032 (1.883-2.192); and all-cause mortality, 1.335 (1.302-1.369), 1.703 (1.635-1.774), 1.959 (1.855-2.068) and 2.092 (1.945-2.250). Within the same proteinuria burdens, late-positive proteinuria was associated with worse outcomes than early-positive proteinuria. The proteinuria burden was dose-dependently associated with clinical outcomes in patients with diabetes. Even a single positive dipstick test requires active management.