Phosphate in Paediatric Health and Disease 1st Edition

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 PREFACE
Phosphorus is the second member of the nitrogen family of elements. Its
atomic number is 15 and its atomic weight is 30.9738. Phosphorus was
discovered in 1669 by the German alchemist Hennig Brandt from a residue
of evaporated urine during his search for the elusive philosophers' stone. The
name phosphorus comes from the Greek "phosphoros" which means "light-
bringing" and was given to the element because of its spontaneous ignition
in air. Phosphorus forms the basis of a very large number of compounds, the
most important class of which are the phosphates. For every form of living
plant or animal cell, phosphates play an essential role. The importance of
phosphorus in the metabolism of human osseous and nonosseous tissues has
been well established long ago.
Since its publication in 1979, Helen and her late husband Harold Har-
rison's book Disorders of Calcium and Phosphate Metabolism in Childhood
and Adolescence has served as the reference book for mineral disorders in
the pediatric age group. With the explosion of information regarding mineral
metabolism during the past quarter century, we felt that the time had come
for a new book on these issues. In order to provide state-of-the-art, up-to-
date coverage within the frame of a concise format, we elected to concentrate,
in this book, mainly on phosphate metabolism. Nonetheless, because of the
close interaction between calcium and phosphate, the book also covers ex-
tensive aspects of calcium metabolism and disorders related to calcium ho-
meostasis. We hope that this book will serve as a guide and a standard
reference in the years to come to all those interested in the intriguing fields
of physiology, pathophysiology, and clinical aspects of mineral metabolism
in childhood.
Our task could not have been accomplished without the help of our
colleagues and friends who combined forces with us in writing this book. We
are very much obliged to all of them for their much appreciated contributions.

Uri Alon, M.D.

Kansas City, Missouri
James C. M. Chan, M.D.
Richmond, Virginia
 THE EDITORS
Uri Alon, M.D., is a Professor of Pediatrics in the School of Medicine
at the University of Missouri-Kansas City and a Pediatric Nephrologist at the
Children's Mercy Hospital in Kansas City, Missouri.
Dr. Alon received his M.D. degree from the Hebrew University, Hadassah
Medical School, Jerusalem, Israel in 1975. After he finished his fellowship
training in Pediatric Nephrology at the Medical College of Virginia, Virginia
Commonwealth University, Richmond, in 1983, he was appointed an As-
sistant Professor of Pediatrics at that institution. In 1985 Dr. Alon became a
Senior Lecturer in the Faculty of Medicine at the Technion Institute of Tech-
nology, Haifa, Israel. In 1988 he was appointed as an Associate Professor at
the University of Missouri-Kansas City and became a Professor in 1992.
Dr. Alon is a member of the American Academy of Pediatrics, the Amer-
ican Society of Bone and Mineral Research, the American Society of Ne-
phrology, the American Society of Pediatric Nephrology, the American Fed-
eration for Clinical Research, the International Society of Nephrology, the
International Society of Pediatric Nephrology, the Midwest Society for Pe-
diatric Research, and the Society for Pediatric Research. He is a member of
several regional and national scientific organizations committees and serves
on the editorial board and as a reviewer for several scientific journals.
Dr. Alon is the author of more than 100 papers and 15 chapters in books
and has presented over 50 lectures in national and international meetings. His
current major research interests relate to water, electrolyte and mineral me-
tabolism, and the pathophysiology of kidney diseases.

James C. M. Chan, M.D., is Professor and Chairman, Nephrology

Division, Children's Medical Center, as well as Vice-Chairman of the De-
partment of Pediatrics, Virginia Commonwealth University's Medical College
of Virginia, Richmond, Virginia. Dr. Chan earned his medical degree in 1964
from McGill University, Montreal, Canada, and received his pediatric and
nephrology training at the Mayo Clinic in Minnesota, Oregon Health Sciences
University in Portland, and Babies Hospital/Columbia-Presbyterian Hospital
in New York.
After holding research and clinical appointments at the University of
Southern California's Children's Hospital of Los Angeles, George Washington
University's Children's Hospital National Medical Center in Washington,
D.C., and the National Institutes of Health in Bethesda, Maryland, he joined
the faculty of the Medical College of Virginia in 1977.
Dr. Chan is a diplomat of the American Board of Pediatrics and the Sub-
Board of Pediatric Nephrology and a member of the Editorial Board of Kidney
International, Nephron, Kidney, and Child Nephrology and Urology, as well
as the Medical Director of the National Kidney Foundation of Virginia.
 Dr. Chan's recent research interests have focused on growth hormone
and insulin-like growth factor expression in the growth failure in children
with renal insufficiency, renal tubular acidosis, and X-linked hypophospha-
temic rickets.
Since 1983, Dr. Chan has been the recipient of three research grants from
the National Institutes of Health, including a clinical trial involving 27 uni-
versities in the U.S. and Canada. He is also currently the Program Director
of a Pediatric Nephrology Institutional Training Grant from the National
Institute of Diabetes, Digestive and Kidney Diseases. He has published more
than 250 research and review papers.
 CONTRIBUTORS

Uri Alon, M.D. Geoffrey D. Clarke, Ph.D.

Professor of Pediatrics Assistant Professor
Division of Pediatric Nephrology Department of Radiology
The Children's Mercy Hospital University of Texas Southwestern
University of Missouri at Kansas Medical Center at Dallas
City School of Medicine Dallas, Texas
Kansas City, Missouri
Ronald J. T. Corbett, Ph.D.
Frank G. Boineau, M.D. Assistant Professor
Professor of Pediatrics Department of Radiology
Department of Pediatrics University of Texas Southwestern
Tulane University Medical Center Medical Center at Dallas
New Orleans, Louisiana Dallas, Texas

Ben H. Brouhard, M.D. Jean-Michel Garel, Ph.D.

Director of Research Programs Professor
Departments of Pediatrics, Endocrinologie Moleculaire et
Hypertension/Nephrology, and Metabolique
Heart & Hypertension Universite Pierre et Marie Curie
The Research Institute Paris, France
The Cleveland Clinic Foundation
Cleveland, Ohio James D. Hanna, M.D.
Assistant Professor of Pediatrics
James C. M. Chan, M.D. Department of Pediatrics
Professor and Chairman Medical College of Georgia
Nephrology Division Augusta, Georgia
Children's Medical Center
Medical College of Virginia Aviad Haramati, Ph.D.
Virginia Commonwealth University Professor
Richmond, Virginia Departments of Physiology &
Biophysics and Medicine
Russell W. Chesney, M.D. Georgetown University School of
Le Bonheur Professor and Chair Medicine
Department of Pediatrics Washington, D.C.
The University of Tennessee,
Memphis College of Medicine Zeev Hochberg, M.D., D.Sc.
Le Bonheur Children's Medical Department of Pediatrics
Center Rambam Medical Center
Memphis, Tennessee Haifa, Israel
Paul S. Kurtin, M.D. Dushan J. Martinasek, M.D.
Associate Professor Neonatology Fellow
Children's Hospital of Los Angeles Division of Neonatology
and Department of Pediatrics Department of Pediatrics
University of Southern California University of Cincinnati College of
School of Medicine Medicine and
Los Angeles, California Department of Pediatrics
The Children's Hospital Research
Craig B. Langman, M.D. Foundation
Associate Professor of Pediatrics Cincinnati, Ohio
Division of Nephrology
Children's Memorial Hospital and
Department of Pediatrics Ralph A. Meyer, Jr., Ph.D.
Northwestern University Medical Director
School Biology Division
Chicago, Illinois Orthopaedic Research Laboratory
Department of Orthopaedic Surgery
John E. Lewy, M.D. Carolinas Medical Center
Professor and Chairman and Adjunct Professor of Biology
Department of Pediatrics University of North Carolina at
Tulane University Medical Center Charlotte
New Orleans, Louisiana Charlotte, North Carolina

Robert H. K. Mak, M.D., Ph.D.

Charles E. Mize, M.D., Ph.D.
Assistant Professor Associate Professor
Division of Pediatric Nephrology
Department of Pediatrics
Department of Pediatrics University of Texas Southwestern
Stanford University School of Medical Center at Dallas
Medicine Dallas, Texas
Stanford, California

Morri E. Markowitz, M.D. Susan E. Mulroney, Ph.D.

Associate Professor Research Assistant Professor
Department of Pediatrics Department of Physiology &
Montefiore Medical Center and Biophysics
Albert Einstein College of Georgetown University School of
Medicine Medicine
Bronx, New York Washington, D.C.
Reginald C. Tsang, M.B.B.S. Yoseph Weisman, M.D.
Professor of Pediatrics and Associate Professor
Obstetrics & Gynecology Vitamin Laboratory
Division of Neonatology Ichilov Medical Center and
Departments of Pediatrics and Tel Aviv University
Obstetrics & Gynecology Tel Aviv, Israel
and Director
Division of Neonatology
University of Cincinnati College of
Medicine and
The Children's Hospital Medical
Center
Cincinnati, Ohio Darrell M. Wilson, M.D.
Assistant Professor
Marian Wang, Ph.D. Division of Endocrinology and
Professor Metabolism
Department of Foods and Nutrition Department of Pediatrics
University of Georgia Stanford University
Athens, Georgia Stanford, California
 We would like
to dedicate this book
to our wives,
Michal and Winnie,
and to our children,
Guy, Saggie, and Ellen.
 TABLE OF CONTENTS
Chapter 1
Phosphate Nutrition 1
Marian Wang, James D. Hanna, and James C. M. Chan

Chapter 2
Renal Handling of Phosphate 15
Russell W. Chesney

Chapter 3
Interrelationships of Parathormone, Phosphate, and 1,25(OH)2D3 43
Craig B. Langman

Chapter 4
Fetal and Placenta! Phosphate Metabolism 55
Jean-Michel Garel

Chapter 5
Developmental Aspects of Phosphate Homeostasis 73
Aviad Haramati and Susan E. Mulroney

Chapter 6
Clinical Assessment of Plasma Phosphate and Renal Tubular
Threshold for Phosphate 103
Uri Alon

Chapter 7
Hypophosphatemia and Bone Disease in the Neonatal
Intensive Care Unit 115
Dushan J. Martinasek and Reginald C. Tsang

Chapter 8
Nutritional Hypophosphatemia in Children 145
Frank G. Boineau and John E. Lewy

Chapter 9
Renal Hypophosphatemia 159
Darrell M. Wilson and Uri Alon

Chapter 10
The Young X-Linked Hypophosphatemic (Hyp) Mouse 193
Ralph A. Meyer, Jr.
Chapter 11
Hypophosphatemia in Disorders of the Parathyroid
Hormone and Vitamin D Metabolism 207
Zeev Hochberg and Yoseph Weisman

Chapter 12
Changes in Serum Phosphate Concentration Due to
Intercompartmental Shifts 223
Ben H. Brouhard

Chapter 13
Renal Hyperphosphatemia 235
Robert H. K. Mak, Paul S. Kurtin, and Uri Alon

Chapter 14
Hormonal Disorders Associated with Hyperphosphatemia 257
Morri E. Markowitz

Chapter 15
Magnetic Resonance in the Investigation of
Intracellular Phosphate 269
Geoffrey D. Clarke, Ronald J. T. Corbett, Charles E. Mize,
and James C. M. Chan

Index 311
 Chapter 1

PHOSPHATE NUTRITION

Marian Wang, James D. Hanna, and James C. M. Chan

TABLE OF CONTENTS

I. Introduction 2

II. Phosphate Homeostasis 3

III. Intestinal Phosphate Absorption 3

IV. Phosphate and Bone 5

V. Cellular Phosphate Stasis 7

VI. Phosphate Nutrition 8

References 10

^H
2 Phosphate in Pediatric Health and Disease

I. INTRODUCTION
Phosphorus is one of the most important inorganic elements, second only
to calcium in abundance in the human body. In humans, approximately 85%
of the total body phosphorus is in bones, 14% in cells and soft tissues, and
1% in extracellular fluids. The phosphorus contained in bone is in the mineral
phase as inorganic orthophosphate and small amounts of inorganic phosphate.
In soft tissue and cell membranes, phosphorus exists mainly as phosphate
esters and to a lesser extent as phosphoproteins and free phosphate ions. In
extracellular fluid, about one tenth of the phosphorus content is bound to
proteins, one third is complexed to sodium, calcium, and magnesium, and
the remainder is present as inorganic phosphate. In biological systems, phos-
phorus is present as phosphate, and these two terms are used interchangeably
in this chapter.
Plasma phosphate and intracellular phosphate have diverse functions.
They take part in the formation of hydroxyapatite, the basic crystalline struc-
ture present in bone. Additionally, they are essential for the process of bone
mineralization. Phosphate serves a vital role in the intermediary metabolism
of carbohydrates, lipids, and proteins. It functions as a cofactor in enzyme
systems and is of paramount importance in the formation of high energy
phosphate compounds. As a component of genetic materials, phosphate is an
essential part of the nucleic acid in chromosomes and ribosomes. Phospho-
lipids are major structural constituents of cell membranes and intracellular
organelles. Phosphate plays a critical role in secondary messenger systems
such as cAMP and phosphatidylinositol, which act as important secondary
messengers that mediate the intracellular effects of various hormones, neu-
rotransmitters, and growth factors. Another important phosphate-containing
compound, diphosphoglycerate, plays a crucial role in oxygen availability/
delivery to the tissue. Phosphate aids in regulating body fluid pH and in
modifying the effects of the B vitamins.
The normal plasma inorganic phosphate concentration ranges between
2.5 and 4.5 mg/dl in adults and between 4.0 and 6.5 mg/dl in children (Chapter
6). The concentration of plasma phosphate varies with dietary phosphate
intake, age and stage of growth, time of day, hormonal effects, and renal
function. Of the total plasma phosphate 88% is ultrafilterable. At pH 7.4,
85% of the ultrafilterable phosphate is in the form of monohydrogen phos-
phate, and the remainder exists mainly as dihydrogen phosphate. Circulating
phosphate is in equilibrium with skeletal and cellular inorganic phosphate as
well as with the organic phosphate formed through the processes of cellular
metabolism. The concentration of inorganic phosphate in the extracellular
fluid is an important factor influencing the mineralization of the skeleton and
cell growth. Inorganic phosphate is a partial determinant of the concentration
of cellular phosphoric esters such as 2,3-diphosphoglycerate in the blood cells
and adenosine triphosphate (ATP) in other cells.