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

Abstract

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) µM and 58.3 (7.5) µM, 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 µM compared with 40.9 µM, 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.

Keywords: diabetes; diabetic nephropathy; hyperglycemia; microvascular complications; nutrition; renal leak; renal threshold; vitamin C.

FIGURE 1

Enrollment and patient flow for vitamin C depletion–repletion study and cross-sectional cohort study of individuals with diabetes and nondiabetic controls.

FIGURE 2

Vitamin C depletion–repletion study in healthy participants. (A, B) Urinary vitamin C excretion as a function of matched plasma vitamin C concentrations in healthy men (A) and women (B). Pharmacokinetic (PK) studies were performed as 1 component of dose–concentration studies (18, 19, 30) by administering intravenous or oral doses (15–1250 mg) of vitamin C on successive days at steady state. Blood samples were obtained at fixed intervals (18, 19). All urine voided during the test period was collected, and each urine void formed a timed collection. The total amount of vitamin C in each urine sample (mg) is indicated on the y-axis. Each symbol shape coupled to a specific color represents a different participant. Data are shown from 10–14 PK studies (5–7 oral doses; 5–7 intravenous doses) for each participant. Participants were 7 men and 10 women. (C) Estimated vitamin C renal threshold values in healthy men (open bar) and women (filled bar) using physiology-based pharmacokinetic modeling [PBPK, mean (SD)]. (D) Vitamin C renal leak criteria for men (open bar) and women (filled bar). Minimal elimination threshold (MET) was defined as 2 SD below mean renal threshold using PBPK modeling (see Methods section). Vitamin C renal leak was defined as abnormal urinary vitamin C excretion (>0.01 mg/total urine volume, limit of detection) occurring when plasma vitamin C concentrations are below MET values of 38.1 µM for men and 43.2 µM for women.

FIGURE 3

Cross-sectional cohort study of vitamin C renal leak in a cohort of individuals with diabetes and nondiabetic controls. (A, B) Urinary vitamin C excretion as a function of plasma vitamin C concentrations in the diabetes cohort (n = 82, A) and nondiabetic control group (n = 80, B). In all panels, each circle represents each participant with a renal leak (yellow) or without a renal leak (blue), assessed using matched urine and plasma vitamin C measurements. (C) Plasma vitamin C concentrations in the diabetes cohort compared with the nondiabetic control group. Square indicates estimated shift in mean plasma vitamin C with horizontal points indicating 95% CI. P values are shown for estimated shift, unadjusted and adjusted for sex, n = 162. (D) Vitamin C renal leak prevalence in the diabetes cohort compared with nondiabetic controls. Square indicates odds ratio with horizontal line indicating 95% CI, n = 162. (E) Demographics and clinical variables associated with vitamin C renal leak. All participants were included in the analysis. Squares indicate odds ratio with horizontal points indicating 95% CI, n = 162. Diuretic use includes loop diuretics, thiazides, and aldosterone antagonists. ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration; PCR, protein/creatinine ratio.