Session/Event: Micronutrients: From Bioavailability to Metabolism and Beyond (Oral 31)

(OR31-03-22) Vitamin C Urinary Loss in Fabry Disease: Clinical and Genomic Factors of Vitamin C Renal Leak

On Demand

Presenting Author(s)

IE

Ifechukwude C. Ebenuwa, MD

Research Physician
Intramural Research Program, NIDDK, NIH
Bethesda, Maryland, United States

Disclosure: Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

View Presentation

Co-Author(s)

PV

Pierre-Christian Violet, Ph.D

Research Fellow
NIH
Bethesda, Maryland, United States
SP

Sebastian Padayatty, MD

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
HT

Hongbin Tu, Ph.D

NIH
Bethesda, Maryland, United States
YW

Yaohui Wang, MD

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
PE

Peter Eck, PhD

University of Manitoba, Canada
KW

Kenneth Wilkins

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
DM

David Moore, MD, PhD

National Institute of Neurological Disorders and Stroke (NINDS)
RS

Raphael Schiffmann, MD

National Institute of Neurological Disorders and Stroke (NINDS)
ML

Mark Levine, M.D.

Senior Investigator, Chief of Molecular and Clinical Nutrition Section
Intramural Research Program, NIDDK, NIH
Bethesda, Maryland, United States

Objectives: Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C excretion: a renal leak. We hypothesized that vitamin C renal leak may be the consequence of disease-mediated dysregulation affecting the renal tubules, resulting in aberrant vitamin C renal reabsorption and increased urinary loss. The study objective was to investigate the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal storage disease associated with renal tubular dysfunction and low plasma vitamin C concentration.

Methods: This was a non-randomized cross-sectional cohort study of males with Fabry disease (n=34) and healthy male controls (n=33). To determine primary outcome of vitamin C renal leak, matched urine and fasting plasma vitamin C measurements were obtained following an overnight fast. Based on data from healthy men, vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38µM. Exploratory outcomes assessed the association between renal leak and clinical parameters; and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1. Proof-of-concept studies were conducted using two mouse models.

Results: Compared with healthy men, Fabry cohort had 16-fold higher odds of renal leak (6% vs 52%: OR16, p< 0.001). Renal leak was associated with higher protein creatinine ratio (p=0.01), lower hemoglobin (p=0.002) and hematocrit (p=0.008). Renal leak, but not plasma vitamin C, was associated with a non-synonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (p=0.01 and p=0.47 respectively). Using two mouse models, we recapitulated the relationships between renal leak, dysregulated vitamin C renal reabsorption and low plasma vitamin C concentrations.

Conclusions: Increased prevalence of vitamin C renal leak in Fabry disease may result from dysregulated vitamin C renal physiology, with significant clinical and genomic associations. Renal leak may be more sensitive than plasma vitamin C in evaluating genomic associations in small cohorts.

Funding Sources: Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD 20892-1372