Kathleen Hering-Smith, MS, PhD, FASN

• Kidney Epithelial Transport Physiology and the relationship to Aging and Disease, specifically in Kidney Stones and Hypertension

Calcium nephrolithiasis remains a frequent and serious cause of morbidity and health care costs. As is well known, urinary citrate is the most important inhibitor of calcium stones in the kidney because citrate, a tricarboxylate, keeps calcium soluble in the urine. The regulation of citrate transport in the kidney has received inadequate investigation and remains poorly understood at the cell and molecular level. Urinary citrate excretion is primarily determined by its fractional reabsorption in the proximal tubule. The dicarboxylate transporter (NaDC1) cloned by Pajor has been considered the main mechanism of apical reabsorption of filtered citrate. Knockout mice, without NaDC1, are viable with normal kidney anatomy, have no severe phenotype, and appear to have significant residual citrate reabsorption. Our recently published studies in OK cells demonstrate a novel mechanism which may explain the remaining citrate reabsorption. This mechanism is sensitive to calcium and magnesium by decreasing citrate transport with increasing concentrations of these ions, and may explain the increase in citrate excretion with increases in urinary calcium found in vivo in both humans and animals. In our published studies utilizing OK (opossum kidney) cells and in our preliminary studies utilizing mouse S1 and S2 proximal tubule cell lines, citrate transport increases significantly when apical calcium is acutely decreased. Thus, our in vitro studies correspond to the in vivo observations made decades ago in humans, demonstrating that urinary citrate normally increases with urinary calcium. This physiological process is a key mechanism that prevents calcium stone formation. We have shown NaDC1 is not sensitive to calcium. What is not known is how the level of calcium in the urine regulates the transport of citrate and the contributions of the known and novel transporters. Without this knowledge we will not be able effectively target citrate transport to protect against nephrolithiasis.

Our long-term goal is to understand the physiological mechanisms leading to the development of calcium stones in order to discover treatment and prevention strategies. Our overall objective is to determine the mechanisms and regulation of apical citrate transport via a novel apical calcium-sensitive transporter, and the relative roles of NaDC1, NaDC3 and SLC26A6. Our central hypothesis is that the novel apical calcium-sensitive citrate reabsorptive process limits citrate transport in the proximal tubule when calcium is increased. This hypothesis is based on our published and preliminary data. The rationale that underlies this line of research is that the elucidation of previously unidentified citrate transporters can potentially lead to new methods of specific inhibition of proximal reabsorption of citrate, enabling increase of urinary citrate and inhibition of calcium stone formation. Our expected outcomes will establish new paradigms in understanding citrate reabsorption in the kidney proximal tubule, and how these paradigms are impacted in acidosis and hypercalciuria. These outcomes are expected to have an important impact since understanding the regulation of citrate transport in the proximal tubule will dramatically improve strategies in the prevention of calcium stones.

Lab Members:

Laura Nussdorf - Physiology MS Student and Summer Researcher

Current Funding:
NIH/NIDDK R01 DK095879-01, Project Period: 09/15/2012-08/31/2016
“A New Target for Kidney Stone Prevention: Calcium-Sensitive Transport of Citrate.”