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Renal calcium and uric acid handling and kidney stones

English title Renal calcium and uric acid handling and kidney stones
Applicant Bonny Olivier
Number 133648
Funding scheme SNSF Professorships
Research institution Division de Néphrologie et d'Hypertension CHUV
Institution of higher education University of Lausanne - LA
Main discipline Physiology : other topics
Start/End 01.08.2011 - 31.03.2016
Approved amount 1'525'566.00
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All Disciplines (2)

Discipline
Physiology : other topics
Internal Medicine

Keywords (3)

Calciuria; Uricosuria; Kidney stones

Lay Summary (English)

Lead
Lay summary

Kidney stones constitute an important health issue, in terms of renal colic,felt by about 10% of the population at least once during lifetime; in terms ofcomplications, with significant number of hospitalizations and surgery relatedto kidney stones; in terms of long-term morbidity that may arise from severecomplications (infection, end stage renal disease and dialysis,...) in a fewpatients; and as an overall financial burden for the health system. Moreover,kidney stones can be seen as an early marker of cardiovascular diseases and ofthe metabolic syndrome.

Despite this large and increasing kidney stone epidemic, only a paucity ofeffort is dedicated to research and to the development of new therapeuticalapproaches. We propose a translational research program devoted to unravel howkidneys are handling calcium and uric acid, two of the main constituents ofkidney stones.

Kidneys are key organs in keeping calcium and uric acid in balance. In orderto achieve this goal, tight regulation of several transport mechanisms ismandatory. Recently, several transporters of calcium or uric acid have beendescribed in the kidney, but their precise role in calcium, respectively uricacid homeostasis and in kidney stone formation remain elusive. We propose tostudy the specific role of a calcium transporter (the sodium/calcium exchanger)in renal calcium handling and of a newly discovered uric acid transporter(SLC2A9) in renal uric acid handling. Mouse models in which these transportersare specifically inactivated only in the kidney will be used.

An in-depth characterization of the role of these transporters in vivo mayhelp designating new therapeutical targets.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Ways of calcium reabsorption in the kidney.
Moor MB, Bonny O (2016), Ways of calcium reabsorption in the kidney., in Am J Physiol Renal Physiol, 1337.
[Oxalate: a poorly soluble organic waste with consequences].
Li Y, Bonny O (2015), [Oxalate: a poorly soluble organic waste with consequences]., in Praxis, 353.
Association of urinary calcium excretion with serum calcium and vitamin D levels.
Rathod A, Bonny O, Guessous I, Suter PM, Conen D, Erne P, Binet I, Gabutti L, Gallino A, Muggli F, Hayoz D, Péchère-Bertschi A, Paccaud F, Burnier M, Bochud M (2015), Association of urinary calcium excretion with serum calcium and vitamin D levels., in Clin J Am Soc Nephrol, 452.
Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system.
muller me, Forni Ogna V, Maillard M, Stoudmann C, Zweiacker C, Anex C, Wuerzner G, Burnier M, Bonny O (2015), Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system., in Pflugers Arch, 2413.
Sodium-dependent phosphate transporters in osteoclast differentiation and function.
Albano G, Moor M, Dolder S, Siegrist M, Wagner CA, Biber J, Hernando N, Hofstetter W, Bonny O, Fuster DG (2015), Sodium-dependent phosphate transporters in osteoclast differentiation and function., in PLoS One, e0125104.
[Kidney stone as a cardiovascular risk marker].
Ernandez T, Bonny O (2014), [Kidney stone as a cardiovascular risk marker]., in Rev Med Suisse, 1656.
Expression, purification, and structural insights for the human uric acid transporter, GLUT9, using the Xenopus laevis oocytes system.
Clémençon B, Luscher BP, Fine M, Baumann MU, Surbek DV, Bonny O, Hediger MA (2014), Expression, purification, and structural insights for the human uric acid transporter, GLUT9, using the Xenopus laevis oocytes system., in PLoS One, 0108852.
Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes.
Bonny O Bochud M. (2014), Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes., in Nephrol Dial Transplant., iv55.
Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow.
Bonny O Edwards A. (2013), Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow., in Am J Physiol Renal Physiol, 304(5), F585-600.
Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.
O'Seaghdha CM Wu H Yang Q Kapur K Guessous I Zuber AM Köttgen A Stoudmann C Teumer A Kutali (2013), Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations., in PLoS Genet., e1003796.
Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets
Wöhrle S Henninger C Bonny O Thuery A Beluch N Hynes NE Guagnano V Sellers WR Hofmann F Kne (2013), Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets, in J Bone Miner Res, 28(4), 899-911.
Renal stone disease: collaborative management between primary care and specialized physicians
Ernandez T Stoermann Chopard C Bonny O Iselin C Martin PY Jaeger P. (2013), Renal stone disease: collaborative management between primary care and specialized physicians, in Rev Med Suisse., 456.
Coordinated regulation of TRPV5-mediated Ca2+ transport in primary distal convolution cultures.
van der Hagen E.A. Lavrijsen M. van Zeeland F. Praetorius J. Bonny O. Bindels R.J. and J, Coordinated regulation of TRPV5-mediated Ca2+ transport in primary distal convolution cultures., in Pflugers Arch..
Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1).
Albano G Dolder S Siegrist M Mercier-Zuber A Auberson M Stoudmann C Hofstetter W Bonny O Fus, Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1)., in Pflugers Arch., 469(2), 225-233.
Urine Fetuin-A is a biomarker of autosomal dominant polycystic kidney disease progression.
Piazzon N, Bernet F, Guihard L, Leonhard WN, Urfer S, Firsov D, Chehade H, Vogt B, Piergiovanni S, Peters DJ, Bonny O, Constam DB, Urine Fetuin-A is a biomarker of autosomal dominant polycystic kidney disease progression., in J Transl Med, 2015 Mar 30(13), 103.

Collaboration

Group / person Country
Types of collaboration
Institute of Biochemistry, Uni Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Friedrich Mischer Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
IUMSP, Université de Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut des Cordeliers, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Novartis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Institut de Physiologie, Université de Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Experimental Biology annual meeting Talk given at a conference Systematic Characterization of SLC2A9 (Glut9) Variants Associated with Serum Uric Acid Levels 30.03.2015 Boston, United States of America Ruiz Anne;
Fourth International Symposium of the NCCR Kidney.CH on Kidney Stones Talk given at a conference Kidney stone at 40, myocardial infarct at 60? Kidney stone as cardiovascular risk factor 20.06.2014 Lausanne, Switzerland Stoudmann Candice; Bonny Olivier; Auberson Muriel; Ruiz Anne;
51th ERA-EDTA congress, European Renal Association Talk given at a conference Renal Calcium Handling and Kidney Stone 02.06.2014 Amsterdam, Netherlands Bonny Olivier;
XVII International Congress on nutrition and metabolism in renal disease Talk given at a conference Update in uric acid handling 07.05.2014 Würzburg, Germany Bonny Olivier;
5ème forum de la recherche médicale, Faculté de Médecine de Sfax, Tunisie Talk given at a conference De la chronobiologie à la chronothérapie : L'horloge interne en physiologie et dans les aspects thérapeutiques 18.04.2014 Sfax, Tunisia Bonny Olivier;
Annual meeting, American Society of Nephrology Talk given at a conference Mice with Kidney-specific deletion of the Sodium/Calcium Exchanger 1 have increased intestinal calcium absorption 08.11.2013 Atlanta, United States of America Bonny Olivier;
3rd international symposium of the NCCR Kidney.CH Talk given at a conference CH=Calcium Homeostasis. Kidney and Bone Perspectives 20.06.2013 Zurich, Switzerland Ruiz Anne; Bonny Olivier; Stoudmann Candice; Li Wenjun; Auberson Muriel;
50th ERA-EDTA congress, European Renal Association Talk given at a conference Update on Uric Acid handling 19.05.2013 Istanbul, Turkey Ruiz Anne; Bonny Olivier;
3ème rencontre de physiologie rénale, Paris / Lausanne Talk given at a conference Kidney Stone and renal handling of Uric Acid and Calcium 29.03.2013 Paris, France Bonny Olivier;
9ème réunion néphrologique Rhône-Alpes Talk given at a conference Acide urique et hypertension : nouvelles données animales 02.02.2013 Champéry, Switzerland Bonny Olivier;
Working group on inherited kidney diseases of the ERA-EDTA Talk given at a conference Tubular disorders involving uric acid 14.12.2012 Zurich, Switzerland Bonny Olivier;
Swiss Society of Nephrology, annual meeting Talk given at a conference Calcium and Magnesium, the Handi-valent 05.12.2012 Zurich, Switzerland Bonny Olivier; Ruiz Anne; Li Wenjun;
Annual meeting, American Society of Nephrology Talk given at a conference Furosemide-induced increase of PTH is mediated by the CaSR in humans 02.11.2012 San Diego, USA, United States of America Bonny Olivier;
49th ERA-EDTA annual meeting Talk given at a conference Uric acid: from GWAS to Mendelian disorders 24.05.2012 Paris, France Bonny Olivier; Auberson Muriel;
3rd European workshop on Crystals and human diseases Talk given at a conference Animal models of uric acid handling 08.03.2012 Paris, France Bonny Olivier;


Self-organised

Title Date Place
4ème rencontres franco-suisse de physiologie rénale 19.03.2014 Lausanne, Switzerland
2ème rencontre Paris-Lausanne des physiologistes rénaux 29.03.2012 Lausanne, CHUV, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Groupe Romand des Diététicien-ne-s de Néphrologie Talk 17.06.2014 Lausanne, Switzerland Bonny Olivier;
Grand Round, Department of Medicine, CHUV, Lausanne Talk 22.05.2014 Lausanne, Switzerland Bonny Olivier;
Colloque du Département de Médecine, Hôpital du Jura, Delémont Talk 23.04.2014 Delémont, Switzerland Bonny Olivier;
Colloque du Service d’Urologie, CHUV Talk 14.11.2013 Lausanne, Switzerland Bonny Olivier;
Colloque du Service d’Endocrinologie, CHUV Talk 28.05.2013 Lausanne, Switzerland Bonny Olivier;
Colloque du Service d’Endocrinologie, CHUV Talk 26.02.2013 Lausanne, Switzerland Bonny Olivier;
Nephro Winterschule Talk 11.01.2013 Murten, Switzerland Bonny Olivier;
Colloque de Rhumatologie, CHUV Talk 20.12.2012 Lausanne, Switzerland Bonny Olivier;
Colloque de médecine Talk 22.11.2012 Hôpital de Morges, Morges, Switzerland Bonny Olivier;
Colloque romand de néphrologie Talk 08.11.2012 Lausanne, Switzerland Bonny Olivier;
Hôpital du Nord Vaudois, site de St-Loup Talk 04.10.2012 Pompaples, Switzerland Bonny Olivier;
Minisymposium Nephrologie Talk 25.09.2012 Bern, Switzerland Bonny Olivier;
Colloque du Département de Médecine Talk 26.10.2011 Delémont, Switzerland Bonny Olivier;
Formation continue des laborantines Talk 15.09.2011 Pompaples, Switzerland Bonny Olivier;


Self-organised

Title Date Place
Minisymposium on Tuberous Sclerosis Complex 26.03.2014 Lausanne, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Approche pratique de la lithiase: duo entre généralistes et spécialistes Revue Médicale Suisse Western Switzerland 2013

Awards

Title Year
Best abstract 2012

Associated projects

Number Title Start Funding scheme
163340 Renal calcium and uric acid handling and kidney stones 01.10.2015 Project funding (Div. I-III)
163340 Renal calcium and uric acid handling and kidney stones 01.10.2015 Project funding (Div. I-III)

Abstract

Kidney stones bring excruciating pain to 10% of the population at least once in their lifetime and represent an increasing and significant burden for the health system. Eighty-five percent of kidney stones are made of calcium and 10% of uric acid, and hypercalciuria and hyperuricosuria constitute two major risk factors for stone formation. The therapeutical armamentarium for kidney stone is limited and basic research is poorly supported in the field. This grant request aims at boosting a translational research program addressing critical aspects of renal calcium and uric acid handling related to kidney stone formation, and developing new therapeutical approaches. Two independent projects addressing timely and key questions on renal calcium handling (project A) and on uric acid handling (project B) are presented here with their specific aims.Project A. Renal calcium handling and hypercalciuria.The final control of renal calcium reabsorption takes place in the distal convoluted and connecting tubules (DCT/CNT) of the nephron, where calcium is reabsorbed through apical calcium channels (TRPV5/6), and basolateral sodium/calcium exchangers (NCX1) and calcium ATPases (PMCA). The role of NCX1 in this process is elusive, but a mathematical model of calcium reabsorption in the DCT/CNT predicts that NCX1 maybe a major regulator of transepithelial calcium transport.•Aim A1. Role of NCX1 in calcium handling. I established a NCX1 kidney-specific knockout mouse model (NCX1(fl/fl;KSP-cre)), and showed that these mice are hypercalciuric, thus verifying the importance of NCX1 in renal calcium handling. In order to identify new regulatory mechanisms of calcium reabsorption, I propose to analyze the transcriptome of microdissected DCT/CNT tubules isolated from control and NCX1(fl/fl;KSP-cre) mice. New regulatory pathways will be studied in vitro and in vivo. •Aim A2. NCX1 and the hypocalciuric effect of thiazides. Thiazides are diuretics acting on DCT cells that are widely used as kidney stone preventive treatment, due to their stimulatory effect on calcium reabsorption by an unknown mechanism. Thiazides may produce their hypocalciuric effect by interfering with the sodium/calcium exchange in the DCT/CNT and NCX1. This hypothesis will be tested on NCX1(fl/fl;KSP-cre) mice.•Aim A3. Calcium-oxalate kidney stone prevention by sodium thiosulfate. Sodium thiosulfate was effective in treating kidney stone formers in small series, but concerns about side effects on bones have been raised. Sodium thiosulfate will be given to a calcium-oxalate stone forming mouse model that will be developed from the hypercalciuric NCX1(fl/fl;KSP-cre) mice. Measured outcomes will be the number of stones and the bone phenotype.Project B. Uric acid handling and hyperuricosuria.Glut9 (SLC2A9) is a recently identified urate transporter which is expressed in the kidney. Transepithelial Glut9-mediated urate transport is poorly understood in the kidney.•Aim B1. Localization and sorting of Glut9 isoforms in the kidney. Precise description of the localization and sorting of the two known Glut9 isoforms will be assessed in the kidney and in DCT/CNT cells, using isoform-specific antibodies newly developed.•Aim B2. Glut9 structure/function. Domains and residues critical for urate transport will be studied in the Xenopus oocyte expression system. •Aim B3. In vivo role of Glut9 in the mouse kidney. Glut9 kidney-specific knockout mice will help characterize the precise role of Glut9 in the kidney.The results of this research will have important implications in elucidating the molecular mechanisms of calcium and urate transport in the kidney and identify potential new therapeutical approaches for treating patients suffering of kidney stones.
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