Is “renal leak” of vitamin C an issue for people with diabetes?
Anitra C Carr, The American Journal of Clinical Nutrition, 10 May 2022
Vitamin C (ascorbate) is an essential dietary nutrient with pleiotropic roles in human health and disease. It is a small, water-soluble molecule; thus, in healthy individuals, any excess that is not required by the tissues of the body is removed from the circulation via glomerular filtration and urinary excretion. The kidney tubules contain the sodium-dependent vitamin C transporter 1 (SVCT1), which helps to maintain vitamin C homeostasis through renal reabsorption in times of low dietary intake.
Since the 1940s, attempts have been made to estimate the “renal threshold” of vitamin C, i.e., the plasma concentration above which filtered vitamin C exceeds renal tubular absorptive capacity, resulting in vitamin C being excreted in urine (1). More recently, the question about renal threshold was refined further to include the effects of age and sex (2). These studies were limited, however, by narrow vitamin C dose ranges and the use of older, less specific and sensitive assay methods that are prone to analyte instability and interference.
Over 2 decades ago, Levine et al. (3, 4) completed 2 well-designed vitamin C pharmacokinetic studies in young, healthy volunteers. They investigated the effects of vitamin C doses in the range of 30–2500 mg/d on plasma concentrations and urinary excretion of the vitamin using a sensitive and specific HPLC method to detect the vitamin. In this issue of the American Journal of Clinical Nutrition, Ebenuwa et al. (5) report a reanalysis of these data from which they were able to determine accurate, sex-specific renal thresholds for vitamin C.
For the current research, Ebenuwa et al. (5) used data from 7 males and 10 of 15 females who participated in the earlier studies, estimating the renal threshold for vitamin C using physiology-based pharmacokinetic modeling. Thresholds were determined to be 49 ± 5 µmol/L in males and 58 ± 8 µmol/L in females. Thus, on average, males appear to start losing vitamin C through their urine at lower plasma concentrations than females, although there was significant variability between individuals.
The authors proceeded to define “renal leak” as the presence of urinary vitamin C in individuals with plasma concentrations below the “minimal elimination threshold,” which was set as 2 SD lower than the renal threshold (i.e., <38 µmol/L for males and <43 µmol/L for females) (5). They then applied their “renal leak” criteria to participants with type 1 and 2 diabetes mellitus (T1DM and T2DM), as people with diabetes are known to have lower vitamin C status than healthy controls (6). Several mechanisms have been proposed for the lower vitamin C status of people with diabetes, including enhanced inflammation and oxidative stress, which can deplete vitamin C; higher body weight, resulting in volumetric dilution of the vitamin; and possible “renal leak” due to diabetic kidney disease (7–9).
To assess “renal leak” in the current study, Ebenuwa et al. (5) recruited 82 participants with T1DM and T2DM and compared these with 80 nondiabetic participants. Plasma vitamin C concentrations were lower in people with diabetes compared with those without diabetes (41 µmol/L compared with 53 µmol/L, respectively). The study did not record either recent or habitual dietary vitamin C intake; thus, the study was not designed to explore potential reasons behind this difference in plasma vitamin C. Applying the sex-specific “minimal elimination thresholds” described above and defining “renal leak” as ≥0.01 mg vitamin C in urine after a 1-h fasting collection, the proportion of participants with “renal leak” was significantly higher in people with diabetes relative to controls (33% compared with 9%, respectively). Furthermore, glycemic control, microvascular/macrovascular complications, obesity, and proteinuria were predictive of vitamin C “renal leak,” indicating involvement of diabetic complications.
Two previous studies have described urinary vitamin C in people with diabetes. One small study comparing urine and plasma vitamin C in T1DM with healthy controls suggested higher urinary vitamin C concentrations in people with diabetes compared with controls when considering differences in between-group plasma concentrations (8). Another study in participants with diabetic nephropathy, defined as an increase in albuminuria, showed that participants with macroalbuminuria had lower plasma vitamin C and higher vitamin C renal clearance compared with those with microalbuminuria (9). There are thus consistencies in the findings of the current and previous studies, which show differences in renal handling of vitamin C between people with diabetes and controls, and a tendency to greater renal leak of vitamin C in those with diabetic kidney disease. These studies used urinary albumin as a marker of diabetic kidney disease, but urinary albumin reflects predominately glomerular damage, rather than tubular dysfunction, which is also a feature of diabetic kidney disease (10). Given the pivotal role of SVCT1 within the proximal tubules for vitamin C reabsorption, future diabetes studies might benefit from the inclusion of markers of proximal tubular diabetic kidney injury.
The pathophysiologic relevance of the findings of Ebenuwa et al. (5) is unclear. Their lower limit of urinary vitamin C of ≥0.01 mg/h reflects the limit of detection of their sensitive HPLC method, however, a handful of participants excreted ∼1.0 mg/h. Assuming consistent excretion of vitamin C over 24 h, excretion of between 0.01 and 1.0 mg vitamin C per hour equates to an estimated daily loss of 0.24–24 mg of vitamin C. This is a modest amount overall, given that the average US vitamin C dietary intake is 75 mg/d (11).
Determining the clinical importance of urinary vitamin C leak in people with diabetes will require a broader understanding of the magnitude of the leak relative to dietary intakes in real-world settings. This information is currently lacking. Ebenuwa et al. (5) measured fasting urinary vitamin C excretion, thereby ensuring methodologic consistency between participants. While acknowledging the practical difficulties associated with collecting serial timed blocks and 24-h urine samples, collections that include postprandial as well as postabsorptive urinary vitamin C would provide invaluable information about the magnitude of this leak.
Overall, the clinical relevance of “renal leak” in people with diabetes will depend on the magnitude of the leak. This is likely to be greatest in those with more severe complications. Meta-analysis has indicated that supplementation with vitamin C may improve early renal damage and thus potentially attenuate renal leak (12). The optimal doses of vitamin C for people with diabetes, both with and without renal leak, are yet to be determined.
