Abnormal urinary loss of vitamin C in diabetes: prevalence and clinical characteristics of a vitamin C renal leak

Background Diabetes is associated with low plasma vitamin C concentrations. Objectives We investigated the contribution of dysregulated vitamin C renal physiology, its prevalence, and associated clinical characteristics. Methods An essential prerequisite was determination of normal vitamin C renal threshold, the plasma concentration at which vitamin C first appears in urine. Using data from 17 healthy participants who underwent vitamin C depletion-repletion studies with a vitamin C dose range of 15-1250 mg daily, renal threshold was estimated using physiology-based pharmacokinetics modeling. Applying renal threshold 95% CIs, we estimated the minimal elimination threshold, the plasma concentration below which no vitamin C was expected in urine of healthy people. Renal leak was defined as abnormal presence of vitamin C in urine with plasma concentrations below the minimal elimination threshold. Criteria were tested in a cross-sectional cohort study of individuals with diabetes (82) and nondiabetic controls (80) using matched plasma and urine samples. Results Vitamin C renal thresholds in healthy men and women were [mean (SD)] 48.5 (5.2) mu M and 58.3 (7.5) mu M, respectively. Compared with nondiabetic controls, participants with diabetes had significantly higher prevalence of vitamin C renal leak (9% compared with 33%; OR: 5.07; 95% CI: 1.97, 14.83; P < 0.001) and 30% lower mean plasma vitamin C concentrations (53.1 mu M compared with 40.9 mu M, P < 0.001). Fasting plasma glucose, glycosylated hemoglobin A1c, BMI, micro/macrovascular complications, and protein/creatinine ratio were predictive of vitamin C renal leak. Conclusions Increased prevalence of vitamin C renal leak in diabetes is associated with reduced plasma vitamin C concentrations. Glycemic control, microvascular complications, obesity, and proteinuria are predictive of renal leak.