EDITORIAL URRENT C OPINION
The pursuit of truth and beauty David A. Bushinsky a and Myles Wolf b
Years ago, understanding mineral metabolism was not difficult. Bone was simply a repository of calcium and phosphorus built by osteoblasts and broken down by osteoclasts. The intestine absorbed these ions and the kidney excreted the excess. There were only a few hormones to consider and each behaved in a logical manner, stimulating divalent ion conservation or excretion as appropriate. As long as ion concentration and skeletal integrity were reasonable, all was well. However, the more we studied mineral metabolism the more we learned that this is a very complex system that not only regulates divalent ions and bone homeostasis but also is integral to disordered cardiovascular biology and ultimately mortality. Led by curiosity, intuition and the work of predecessors, the scientists who were asked to write in this issue of Current Opinion have led efforts to understand mineral metabolism especially when the main excretory channel for ion elimination and the source for 1,25(OH)2D, namely the kidney, fails. The goal, as always, is to uncover truth, which can lead to effective treatment and the betterment of patients’ lives. Ming Chang Hu, Makoto Kuro-o and Orson Moe start the issue with a lucid presentation of aKlotho and vascular calcification. It is known that chronic kidney disease (CKD) is a state of aKlotho deficiency. They present the newest data on the role of aKlotho in preventing vascular calcification and urge understanding of its effects on overall vascular biology rather than on single isolated cells. We predict that the comprehensive figure from their article will be used by many lecturers to help explain the role of aKlotho deficiency in vascular calcification. The next two articles in this issue move from aKlotho to fibroblast growth factor 23 (FGF23). Marta Christov describes the elevation of FGF23 in patients with acute kidney injury and its correlation with mortality. The elevation appears related to increased production and decreased clearance of FGF23 and does not appear to be a function of changes in parathyroid hormone or 1,25(OH)2D. Seiji Fukumoto then discusses the exciting new work on FGF23 neutralizing antibodies. X-linked hypophosphatemic rickets and related diseases cause
considerable morbidity as a result of FGF23 excess. Inactivation of this hormone, utilizing specific antibodies, holds promise as precisely directed, effective treatment. The importance of understanding basic biology as the cornerstone of rational therapy has never been more evident than in this work. We then present articles relating to four principal ions: calcium, magnesium, phosphorus and sodium. Hakan Toka writes on the calcium-sensing receptor, especially its role in regulation of paracellular calcium transport in the thick ascending limb of Henle. He describes how CaSR-deficient mice were utilized to understand how changes in extracellular calcium alter calcineurin, NFATc1, microRNAs and ultimately claudin 14 expression, which regulates paracellular tubular calcium reabsorption. Again a beautiful figure illustrates these pathways. Jenny van der Wijist, Rene Bindels and Joost Hoenderop write about the importance of magnesium homeostasis and how transient receptor potential melastatin 6 regulates magnesium entry in the distal convoluted tubule and thereby controls magnesium balance. They describe the factors and hormones that control cellular transcription, membrane expression and function. Two figures elegantly illustrate these pathways. Mark Hannon and Joseph Verbalis then write about how skeletal bone, which is a large repository of body sodium, may play a role in overall body sodium homeostasis. Hyponatremia may decrease bone density and quality, which, coupled to hyponatremia-induced gait instability, leads to fractures. Bone, through buffering body sodium, may improve hyponatremia in the short term, but ultimately leads to adverse longterm consequences. Yves Sabbagh and Susan Schiavi
a Division of Nephrology, University of Rochester Medical Center, Rochester, New York and bDivision of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Correspondence to David A. Bushinsky, MD, John J. Kuiper Distinguished Professor of Medicine, Chief, Nephrology Division, University of Rochester Medical Center, 601 Elmwood Ave., Box 675, Rochester, New York 14642, USA. E-mail: [email protected]; myles.wolf @northwestern.edu Curr Opin Nephrol Hypertens 2014, 23:329–330 DOI:10.1097/01.mnh.0000447025.97464.ea
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mineral metabolism
write about intestinal phosphate absorption through Npt2b. Using knockout mice, they provide evidence that Npt2b may also be a phosphate sensor and involved in organ cross-talk. They describe studies demonstrating that inhibition of Npt2b may be a suitable tool to prevent phosphate overload in patients with CKD. Finally, Xianojing Tang and John Lieske write about the acute and chronic injury that is induced by nephrolithiasis. Obstruction by stones and crystals may result in acute kidney injury that becomes chronic if flow is not restored in a reasonable period of time. They describe how nephrolithiasis is a small yet independent risk factor for CKD and end-stage renal disease. As Albert Einstein said, ‘The pursuit of truth and beauty is a sphere of activity in which we are permitted to remain children all our lives’. Children,
330
www.co-nephrolhypertens.com
like outstanding scientists, are curious, not restrained by prejudice and are able to pursue truth and beauty to understand a small portion of the universe. We present to you the latest thinking in this complex world of mineral metabolism. We challenge each of you, especially those who are just entering this arena, to remain as children, open to new ideas and concepts and unrestrained by previous assumptions, and to ultimately refine and revise the thoughts that you find on these pages to uncover the truth and beauty of this complex system. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
Volume 23 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The pursuit of truth and beauty David A. Bushinsky a and Myles Wolf b
Years ago, understanding mineral metabolism was not difficult. Bone was simply a repository of calcium and phosphorus built by osteoblasts and broken down by osteoclasts. The intestine absorbed these ions and the kidney excreted the excess. There were only a few hormones to consider and each behaved in a logical manner, stimulating divalent ion conservation or excretion as appropriate. As long as ion concentration and skeletal integrity were reasonable, all was well. However, the more we studied mineral metabolism the more we learned that this is a very complex system that not only regulates divalent ions and bone homeostasis but also is integral to disordered cardiovascular biology and ultimately mortality. Led by curiosity, intuition and the work of predecessors, the scientists who were asked to write in this issue of Current Opinion have led efforts to understand mineral metabolism especially when the main excretory channel for ion elimination and the source for 1,25(OH)2D, namely the kidney, fails. The goal, as always, is to uncover truth, which can lead to effective treatment and the betterment of patients’ lives. Ming Chang Hu, Makoto Kuro-o and Orson Moe start the issue with a lucid presentation of aKlotho and vascular calcification. It is known that chronic kidney disease (CKD) is a state of aKlotho deficiency. They present the newest data on the role of aKlotho in preventing vascular calcification and urge understanding of its effects on overall vascular biology rather than on single isolated cells. We predict that the comprehensive figure from their article will be used by many lecturers to help explain the role of aKlotho deficiency in vascular calcification. The next two articles in this issue move from aKlotho to fibroblast growth factor 23 (FGF23). Marta Christov describes the elevation of FGF23 in patients with acute kidney injury and its correlation with mortality. The elevation appears related to increased production and decreased clearance of FGF23 and does not appear to be a function of changes in parathyroid hormone or 1,25(OH)2D. Seiji Fukumoto then discusses the exciting new work on FGF23 neutralizing antibodies. X-linked hypophosphatemic rickets and related diseases cause
considerable morbidity as a result of FGF23 excess. Inactivation of this hormone, utilizing specific antibodies, holds promise as precisely directed, effective treatment. The importance of understanding basic biology as the cornerstone of rational therapy has never been more evident than in this work. We then present articles relating to four principal ions: calcium, magnesium, phosphorus and sodium. Hakan Toka writes on the calcium-sensing receptor, especially its role in regulation of paracellular calcium transport in the thick ascending limb of Henle. He describes how CaSR-deficient mice were utilized to understand how changes in extracellular calcium alter calcineurin, NFATc1, microRNAs and ultimately claudin 14 expression, which regulates paracellular tubular calcium reabsorption. Again a beautiful figure illustrates these pathways. Jenny van der Wijist, Rene Bindels and Joost Hoenderop write about the importance of magnesium homeostasis and how transient receptor potential melastatin 6 regulates magnesium entry in the distal convoluted tubule and thereby controls magnesium balance. They describe the factors and hormones that control cellular transcription, membrane expression and function. Two figures elegantly illustrate these pathways. Mark Hannon and Joseph Verbalis then write about how skeletal bone, which is a large repository of body sodium, may play a role in overall body sodium homeostasis. Hyponatremia may decrease bone density and quality, which, coupled to hyponatremia-induced gait instability, leads to fractures. Bone, through buffering body sodium, may improve hyponatremia in the short term, but ultimately leads to adverse longterm consequences. Yves Sabbagh and Susan Schiavi
a Division of Nephrology, University of Rochester Medical Center, Rochester, New York and bDivision of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Correspondence to David A. Bushinsky, MD, John J. Kuiper Distinguished Professor of Medicine, Chief, Nephrology Division, University of Rochester Medical Center, 601 Elmwood Ave., Box 675, Rochester, New York 14642, USA. E-mail: [email protected]; myles.wolf @northwestern.edu Curr Opin Nephrol Hypertens 2014, 23:329–330 DOI:10.1097/01.mnh.0000447025.97464.ea
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mineral metabolism
write about intestinal phosphate absorption through Npt2b. Using knockout mice, they provide evidence that Npt2b may also be a phosphate sensor and involved in organ cross-talk. They describe studies demonstrating that inhibition of Npt2b may be a suitable tool to prevent phosphate overload in patients with CKD. Finally, Xianojing Tang and John Lieske write about the acute and chronic injury that is induced by nephrolithiasis. Obstruction by stones and crystals may result in acute kidney injury that becomes chronic if flow is not restored in a reasonable period of time. They describe how nephrolithiasis is a small yet independent risk factor for CKD and end-stage renal disease. As Albert Einstein said, ‘The pursuit of truth and beauty is a sphere of activity in which we are permitted to remain children all our lives’. Children,
330
www.co-nephrolhypertens.com
like outstanding scientists, are curious, not restrained by prejudice and are able to pursue truth and beauty to understand a small portion of the universe. We present to you the latest thinking in this complex world of mineral metabolism. We challenge each of you, especially those who are just entering this arena, to remain as children, open to new ideas and concepts and unrestrained by previous assumptions, and to ultimately refine and revise the thoughts that you find on these pages to uncover the truth and beauty of this complex system. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
Volume 23 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
