Research and discovery leading to the naming of chronic kidney disease — mineral and bone disorder (CKD-MBD) has now celebrated its 50th anniversary. A Phosphate Centric Forum, supported by Genzyme Corporation, was held on 24-25 June 2010 at the Sheraton West Park Hotel, Munich, Germany.

Twenty-seven eminent medical and scientific experts met to discuss the central role of phosphate in the development of CKD-MBD, which was first identified 50 years ago. Topics included the pathophysiology, discoveries such as the vitamin D receptor, calcium-sensing receptor (CaSR), and fibro- blast growth factor 23 (FGF-23), and available treatment options. The experts also discussed future needs regarding research and management of this disorder.

50 Years of Research and Discovery in Chronic Kidney Disease and Mineral & Bone Disorder: The Central Role of Phosphate


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Eduardo Slatopolsky, MD, FACP, Joseph Friedman Professor of Renal Diseases in Medicine, Washington University School of Medicine, St. Louis, MO, USA
Sharon Moe, MD, Professor of Medicine and Vice-Chair for Research, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Presenting Faculty

Roger Bouillon, MD, Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Belgium
David Bushinsky, MD, Professor and Associate Chair of Medicine, Nephrology Unit, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Cyrille Confavreux, MD, Service de Rhumatologie, Université de Lyon-Sud, France
Tilman Drueke, MD, INSERM Unité 845 and Service de Néphrologie, Hôpital Necker, Assistance Publique- Hôpitaux de Paris, and Faculté de Médecine René Descartes, Paris, France
Keith Hruska, MD, Director of Pediatric Nephrology, Washington University School of Medicine, St. Louis, MO, USA
Harald Jüppner, MD, Associate Professor of Pediatrics, Harvard University Medical School, Boston, MA, USA
Makoto Kuro-o, MD, Associate Professor of Pathology and Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
Martin Pollak, MD, Harvard Institutes of Medicine, Department of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
Mariano Rodriguez, MD, Departamento de Medicina, Hospital Universitaria de Reina Sofia, Cordoba, Spain


Ezequiel Bellorin-Font, MD, Venezuela
Tobias Larsson, MD, Sweden
Jorge Cannata-Andía, MD, Spain
Klaas Olgaard, MD, Denmark
Aluizio Carvalho, MD, Brazil
Anthony Portale, MD, USA
Ricardo Correa-Rotter, MD, Mexico
Isidro B. Salusky, MD, USA
David Cunningham, MD, UK
José-Vicente Torregrosa, MD, Spain
Masafumi Fukugawa, MD, Japan
Myles Wolf, MD, USA
Vanda Jorgetti, MD, Brazil
Maria Eugenia Canziani, MD, Brazil

The intact nephron hypothesis: concept to implications

Professor Eduardo Slatopolsky, USA

Professor Slatopolsky presented a summary of the last 50 years of research and discovery starting with the “intact nephron hypothesis:” each individual nephron is either functional or non-functional; as the number of functioning nephrons declines in CKD, there is a lower glomerular filtration rate (GFR). Surviving nephrons undergo adaptations that maintain renal homeostasis, but with a “trade-off.”

Figure 1: Pathogenesis of secondary hyperparathyroidism in CKD-MBD.
Figure 1: Pathogenesis of secondary hyperparathyroidism in CKD-MBD.

Hormones that reach high levels during uremic nephron adaptation exert adverse effects in other systems; thus, much CKD pathology does not result from reduced renal excretion itself, but from attempts to maintain homeostasis in the face of declining GFR, e.g., the increase in parathyroid hormone secretion, which occurs as a consequence of phosphate retention.

In the 1960s, many factors currently known to be involved in renal phosphate physiology were unknown, such as calcitriol, vitamin D receptors, FGF-23 and klotho, discussed later in this program (Figure 1). In the early 1970s, Professor Slatopolsky and colleagues showed that alterations in phosphate metabolism led to secondary hyperparathyroidism (SHPT) and progression of CKD.

Professor Slatopolsky showed that a low-phosphate diet reduces parathyroid hormone levels by reducing the need for nephrons to increase fractional excretion of phosphate; conversely, a high-phosphate diet stimulates adaptation and leads to the down-regulation of calcium receptors in the parathyroid (PT) gland.

He also showed that plasma parathyroid hormone is regulated by duodenal phosphate on a time scale of minutes; low-phosphate duodenal gavage lowers plasma phosphate and parathyroid hormone within 15 minutes, whereas high-phosphate gavage raises plasma parathyroid hormone just as rapidly. Thus, acute regulation of parathyroid hormone in vivo by dietary phosphate may be mediated by a gut-derived hormone— an intestinal ‘phosphatonin.’

Further analysis of this pathway, including the identification of a phosphate sensor and the mediator of the response, will advance our understanding of phosphate homeostasis.

Using a rat model, Professor Slatopolsky showed that enhanced transforming growth factor alpha (TGFα) and its receptor (EGFR) co-expression is a major contributor to parathyroid hyperplasia in early CKD. His group has shown that parathyroid Tumor necrosis factor Alpha Converting Enzyme (TACE) activity is a key determinant of the severity of TGFα/EGFR-driven hyperplasia in SHPT, and dietary phosphate regulates TACE expression.

Questions raised by the participants that remain unanswered to date include the relative importance of a decrease in 1,25(OH)2D levels versus an increase in serum phosphate for hyperplasia of the parathyroid glands; whether there is a phosphate sensor in the parathyroid gland and gut; and the role of phosphate (which can act independently of calcitriol) in modulating vitamin D synthesis in the diseased kidney in early CKD.