Kidney stones constitute an important health issue, in terms of (i) pain (renal colic), felt by about 10% of the population at least once during lifetime; (ii) complications, with significant number of hospitalizations and surgery related to kidney stones; (iii) long-term morbidity that may arise from severe complications (infection, end stage renal disease and dialysis,...) in a few patients; and (iv) as an overall financial burden for the health system. Moreover, kidney stone can be seen as an early marker of cardiovascular diseases and of the metabolic syndrome.
Despite the large and increasing kidney stone epidemic, only a paucity of effort is dedicated to kidney stone research and to the development of new therapeutic approaches. We established a translational research program devoted to unravel how kidneys are handling calcium and uric acid, two of the main constituents of kidney stones.
Kidneys are key organs in keeping calcium and uric acid in balance. In order to achieve this goal, tight regulation of several transport mechanisms is mandatory. Recently, several transporters for calcium or for uric acid have been described in the kidney, but their precise role in calcium, respectively uric acid homeostasis and in kidney stone formation remain elusive. We are studying the specific role of a calcium transporter (the sodium/calcium exchanger, NCX1) in renal calcium handling and of a newly discovered uric acid transporter (SLC2A9) in renal uric acid handling. Mouse models in which these transporters are specifically inactivated in the kidney have been established. We showed that both transporters are key players in calcium and uric acid homeostasis and putative drug target.
Collaborating with Prof. A. Edwards, in Paris, we tested a mathematical model predicting that NCX1 is instrumental in transcellular calcium reabsorption in the distal part of the nephron. And using genome-wide association studies on calcemia, we were part of a huge consortium led by Prof. M. Bochud, which identified new genomic loci associated with the control of calcemia.
Figure legend: Genes involved in regulation of serum calcium concentration. Genes have been identified either previously by studies of monogenic diseases or by GWAS performed on serum calcium and on vitamin D. Genes represented in green are mainly involved in the PTH axis and those in red are mainly involved in the vitamin D axis. (From Bonny, O. and M. Bochud, Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv55-62.)