Calcium

nephrotic
A state
Shaul

G. Massry

metabolism

in patients

syndrome
with vitamin
and

David

A.

D deficiency1

Goldstein2

The American

Journal

of Clinical

Nutrition

intestinal
calcium
absorption,
augmented
calcium
retention
and a rise in serum
calcium
(7, 24) (Fig.
1). In contrast
to these
data,
Mountokalakis
et a!. (26) reported
that intestinal
absorption
of calcium
measured
with
47Ca was normal
in patients
with nephrotic
syndrome
and normal
renal
function
but defective
calcium
absorption
became
evident
when
renal insufficiency
ensued.
Indirect
evidence
suggests
that bone
metabolism
may be abnormal
in patients
with
nephrotic
syndrome,
and the available
information
was obtained
mainly
from
children.
Emerson
and Beckman
(7) reported
generalized rarefaction
of the diaphysis
but the epiphysis
was normal
and growth
rate was not
affected
in two of three
nephrotic
children.
Gottfried
et a!. (8) and Hooft
and Vermassen
(16) also found
that some
of their
children
with
nephrotic
syndrome
had
radiographic
evidence
of bone
demineralization.
Similar
findings
were reported
by Jones
et a!. (21) in
adults.
These
data
were
interpreted
as evidence
for osteoporosis.
However,
Jones
et a!.
(21) studied
the retention
of calcium
in 10
nephrotic
patients
receiving
calcium
infusion.
They
found
that the patients
retained
84
3.8% of the calcium
load as compared
to 27
to 55 (mean
41%) in normal
subjects
(27).
This observation
is consistent
with the presence
of osteomalacia
in the patients
with
nephrotic
syndrome.
Lim et a!. (24) studied
bone
biopsies
from
seven
nephrotics
and
found
that both total bone and osteoid
indices, as defined
by Garner
and Ball (28) were
normal.
From
the Division
of Nephrology
and the Department of Medicine
of the University
of Southern
California School
of Medicine,
Los Angeles,
California
90033.
2 Recipient
of fellowship
from the National
Institutes
of Health
lF32
AM 05754.

31: SEPTEMBER

1978,

pp.

1572-1580.

Printed

in U.S.A.

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

Disturbances
in calcium
metabolism
in patients
with nephrotic
syndrome
are not uncommon.
These
include
hypocalcemia,
hypocalciuria,
defective
intestinal
absorption
of
calcium,
and disorders
in bone
metabolism.
Denis
and Hobson
(1) have noted
as early as
1923 that patients
with nephrotic
syndrome
may
have
hypocalcemia,
and,
since
then,
many
investigators
have confirmed
this finding (2-25).
The hypocalcemia
was attributed
to a decrease
in the fraction
ofcalcium
bound
to albumin
since the blood
levels of the latter
are usUally
reduced
in the nephrotic
syndrome
(2). There
are only limited
and contradictory
data
on the levels
of diffusible
and
ionized
calcium
in these
patients
(5, 11, 15,
21, 22, 25). Normal
(5, 11, 15), low (22, 25),
or elevated
(21) levels
have
been
reported
suggesting
that at least some patients
with the
nephrotic
syndrome
may have true hypocalcemia,
i.e., a fall in the concentration
of ionized
calcium.
This
discrepancy
among
the
results
from various
laboratories
could be due
to the different
methods
used
for the measurements
of these
parameters
and
to the
duration
of the nephrotic
syndrome.
Indeed,
Hooft
et a!. (18)
found
that
the levels
of
serum
calcium
were reduced
proportionately
to the fall in the concentration
of serum
albumin
during
the early
stages
of the nephrotic
syndrome,
and true hypocalcemia
became evident
later in the course
of the disease.
Fecal
calcium
may be high in patients
with
nephrotic
syndrome
(6, 7, 9, 13, 16, 19, 20,
24) suggesting
that net intestinal
absorption
of calcium
may be impaired.
Metabolic
balance
studies
in few patients
have,
indeed,
demonstrated
defective
intestinal
absorption
of calcium
even
when
renal
function
was
normal
(6, 7, 9, 24). Remission
of the nephrotic
syndrome
was followed
by increased
1572

with

CALCIUM

METABOLISM

IN

NEPHROTIC

SYNDROME

1573

4year5

RM

Body weight
Plasma

protein

qm. per cent

calcium

3erum
mg. per

cent

Urinary zodium excretion

meq,

per day

Urinary caldurn excretion

mper

day

Nitrogen

retention

gm.pday

Calcium retention
rn per day

Fho5phorLL5 retention
mg. per
1

Week1

FIG.
1. Effect
of remission
From
Emerson
and Beckman

of the
(7).

6
nephrotic

day

1 i

syndrome

Another
aspect
of calcium
metabolism
evaluated
in few patients
with nephrotic
syndrome
was the calcemic
response
to the administration
of parathyroid
extract.
Scriver
(6) found
that the rise in serum
calcium
in
response
to parathyroid
extract
administration was impaired
in one of his two patients.
In another
patient,
Coffips
ox-parathyroid
extract
in doses
of 0.5 to 3.0 ml did not raise
the concentration
of serum
calcium
and only
larger
doses
administered
for several
days
were
successful
to bring
the level of serum
calcium
to normal
(3). These
data
suggest
that these
patients
may have various
degrees
of skeletal
resistance
to the calcemic
action
of
parathyroid
hormone.
Low urinary
excretion
of calcium
is a very

9
on serum

calcium,

urinary

calcium,

and

calcium

retention.

frequent
finding
in patients
with
nephrotic
syndrome
(4, 6, 7, 9, 13, 17-21,
23-25).
Boyd
et a!. (4) in 1926,
were
the first to draw
attention
to this phenomenon.
The mechanisms
underlying
this hypocalciuria
are not
well understood.
Since the renal
handling
of
calcium
and
sodium
are closely
associated
(29, 30), it is possible
that the hypocalciuria
is due to increased
sodium
retention
usually
present
in these
patients.
Data
supporting
such a postulate
are lacking
and Jones
et a!.
(21) did not find a relationship
between
urinary
calcium
and
sodium
in patients
with
nephrotic
syndrome.
The various
disturbances
in calcium
metabolism
which
are observed
in patients
with
nephrotic
syndrome
and normal
renal
func-

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

phophoru excretion

1574

MASSRY

AND

(23) and Nishi

et al. (40) provide
support
for
this hypothesis.
Schmidt-Gayk
et a!. (23) studied
the binding of 3H 250HD3
by the urine
of patients
with
nephrotic
syndrome.
They
found
that
the bound/free
ratio
at increasing
tracer
dilution
marked!y
exceeded
the bound/free
ratio obtained
by albumin.
These
observations
indicate
that the urine
of nephrotic
patients
NEPHROTIC
SYNDROME

NORMALS

CHRONIC
FAILURERENAL

40

S
U
35

30

.-..
0)

C
0

(J

25

20

0
0
-J

h
#{163}

IS

#{163}
#{163}

#{149}
I
#{163}

FIG.
mal

subjects,

with

renal

2.

Blood

patients

failure

levels of 25-hydroxyvitarnin
with nephrotic
syndrome
but without
proteinuria.

#{149}#{149}.

E
0)

D in norand those

#{149}

#{149}
#{149}

0
0

I0

#{149}.
#{149} #{149}

cJ
0

0
0
-J

#{149}

#{149}

#{149}

#{149} Y4.52X-3.19
#{149}

#{149}#{149}
0

2
SERUM

r:.71

p<.0I

3
ALBUMIN

g/IOOml

FIG.
3. The relationship
between
the blood
25-hydroxyvitamin
D and
the concentration
albumin
in 26 patients with nephrotic
syndrome.
Goldstein
et al. (25).

levels of
of serum
From

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

tion are similar

to those seen in patients
with
chronic
rena! failure.
The latter
patients
also
have
hypocalcemia
(3 1),
hypocalciuria
(3 1-33), defective
intestinal
absorption
of calcium (34, 35), bone disease
(36), and skeletal
resistance
to the calcemic
action
of parathyroid hormone
(37). These
similarities
have
been stressed
by Jones
et a!. (21).
It is well
accepted
that
disturbances
in
vitamin
D metabolism
and a deficiency
of the
active
metabolite(s)
of vitamin
D in patients
with chronic
renal
failure
play a major
role
in the genesis
of the various
derangements
of
calcium
homeostasis
(36). It is theoretically
possible,
therefore,
that a state of vitamin
D
deficiency
also exists
in patients
with
nephrotic
syndrome
and underlies
the various
abnormalities
in calcium
metabolism
detailed
above.
The
metabolite,
250HD3,
circulates
in
blood
bound
to an inter-a
globulin
(38). This
protein
has been purified
and partially
characterized
by Haddad
and Walgate
(39), and
a radioimmunoassay
for its measurements
has also been developed
by these
authors.
It
is called
vitamin
D binding
protein
(DBP).
It
has a smaller
molecular
weight
(---58,000)
than
albumin
(--69,000).
Therefore,
both
DBP and 250HD3
will be !ost in the urine
in
patients
with
the nephrotic
syndrome
and
heavy
proteinuria.
Under
such circumstances
the blood
levels of 250HD3
may fall. Indeed,
Schmidt-Gayk
et a!. (23) and Goldstein
et a!.
(25) found
the blood
levels
of 250HD3
in
patients
with nephrotic
syndrome
are significantly
lower
than
those
in normal
subjects.
The data of Goldstein
et al. are depicted
in
Figure
2. The blood
levels of 250HD3
ranged
between
11.3 to 38.1 (21.8 2.3 SE) ng/ml
in normal
subjects,
1.0 to 18.6 (8.6 1.0)
ng/ml
in patients
with nephrotic
syndrome,
and 1 !.6 to 41.3 (24.8 3.2) ng/ml
in patients
with a comparable
degree
of renal failure
but
without
proteinuria.
The
blood
levels
of 250HD3
in patients
with nephrotic
syndrome
showed
a direct
and
significant
(P < 0.0!)
relationship
with the
levels
of serum
albumin
(Fig.
3), and
an
inverse
and significant
(P < 0.01) relationship
with the magnitude
of the proteinuria
(Fig.
4). These
observations
are consistent
with the
notion
that 250D3
is lost in the urine of these
patients.
The
data
of Schmidt-Gayk
et a!.

GOLDSTEIN

CALCIUM

METABOLISM

IN NEPHROTIC

E
0)
C
U
U

cJ
0

0
0

-J

IN URINE

g/24hr

FIG. 4. The relationship

between
the blood
levels of
25-hydroxyvitamin
D and the degree
of proteinuria
in
26 patients
with nephrotic
syndrome.
The line represents
the best fit obtained
with computer
analysis
of the data
utilizing
a polynomial
equation.
From
Goldstein
et al.
(25).
had high
binding
affinity
for 250HD3
suggesting
the presence
of DBP.
Utilizing
radial
immunodiffusion,
these authors
were able to
find DBP
in the urine
of all their
nephrotic
patients.
Nishi
et a!. (40) studied
the elimination
of
3H 250HD3
in the urine
of rats with experimental
proteinuria
(protein
excretion:
765 to
1310 mg/24
hr). They
found
that 40 to 50%
of the administered
radioactivity
was
excreted
in the urine
of these rats while
only
1
to 2% appeared
in the urine
of the control
animals
(protein
excretion:
27 to 84 mg/24
hr).
These
data
clearly
demonstrate
the
marked
loss of 250HD3
in the urine
in states
with heavy
proteinuria.
Available
data indicate
that the concentration of DBP in blood
is far in excess
of that
needed
for the transport
of the normal
content of vitamin
D and its metabolites
(39). It
has been
estimated
that under
normal
conditions,
less than
5% of the available
high
affinity
vitamin
D binding
sites are occupied.
It is, therefore,
surprising
to find low blood
levels
of 250HD3
even if large
quantities
of
DBP are lost in the urine.
One would
expect

1575

that adequate
amounts
of binding
sites still
be present
in the blood
to maintain
normal
levels
of 250HD3.
At least two possibilities
should
be considered
to explain
this finding.
First,
the 25-hydroxylation
of the parent
vitamin
D by the liver
may
be impaired
in
nephrosis.
The data of Nishi
et a!. (40) vitiate
this possibility
(40). They
found
that the conversion
of laOHD3
to 1a25(OH)2D3
by livers
from
rats with nephrosis
is normal.
Second,
it is possible
that in order
to maintain
normal
blood
levels of 250HD3
in the face of heavy
losses
of DBP in the urine,
the patients
must
have
large
intake
of vitamin
D or 250HD3.
There
are no data
to refute
or confirm
this
contention.
It is very important
to answer
this
question
since it may have important
therapeutic
implications.
A decrease
in the blood
levels of 250HD3
may be accompanied
by a fall in the concentration
of l,25(OH)2D3.
However,
the blood
levels
of 250HD3
at which
a deficiency
of
l,25(OH)2D3
might
occur is not known.
Hahn
et a!. (41) suggested
that vitamin
D deficiency
may occur
when
the blood
levels of 250HD3
falls below
10 ng/ml.
Indeed,
Greenlaw
et a!.
(42) reported
that osteomalacia
was present
in patients
with a blood
level of 250HD3
of
4 to 6 ng/m!.
Eighteen
of the 26 nephrotic
patients
studied
by Goldstein
et al. had blood
levels of 250HD3
below
10 ng/ml
and, therefore,
could
also
have
low blood
levels
of
l,25(OH)2D3.
In addition,
a small
fraction
of
l,25(OH)2D3
in blood
may also be bound
to
DBP
(38) and the loss of the latter
in the
urine
could
also affect
the blood
levels
of
1,25(OH)2D3.
Thus,
the recent
information
on the blood
levels
of 250HD3
in patients
with nephrotic
syndrome
indicate
that a state of vitamin
D
deficiency
does
indeed
exist,
and it may be
responsible
for the various
abnormalities
in
calcium
metabolism
observed
in these
patients.
It is reasonable
to assume
that
both
the
severity
and the duration
of the proteinuria
are critical
factors
in determining
the magnitude
and the chronicity
of the vitamin
D
deficiency
in these
patients.
Unfortunately,
there
are no detailed
data
carefully
documenting
a clear relationship
between
the duration
and magnitude
of proteinuria
on the
one hand
and the blood
levels
of 250HD3

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

PROTEIN

SYNDROME

1576

MASSRY

AND

GOLDSTEIN

the disturbance
in calcium
metabolism
the other.
However,
the observation
of
Hooft
et a!. (18) that true hypocalcemia
occurred
in children
who had nephrotic
syn-

Recent
observations
from our laboratory
indicate
that the vitamin
D deficient
state in

drome

with

and

on

for more

than

two

months

underscores

2 weeks.

nephrotic

nephrotic
syndrome
has pathoconsequences.
In seven patients

syndrome

and

normal

renal

function,
the blood
concentrations
of ionized
calcium
were low in four. The blood
!eve!s of
the amino-terminal
fragment
of PTH in these
seven
patients
displayed
an inverse
relationship with
the concentration
of ionized
calcium (Fig. 6). Although
most of the values
of
PTH

of the

in blood
assay,

were

within

two

of the

elevation
in blood
the concentrations

PTH
of

the normal
patients

levels.
ionized

had

range
frank

Furthermore,
calcium

in

blood
were significantly
lower
(P < 0.01) in
patients
with nephrotic
syndrome
and rena!
failure
than in patients
with comparable
degree of renal
insufficiency
but without
proteinuria
(Table
1). These
observations
underscore the importance
of the low blood
levels
of 250HD3
in the etiology
of the hypocalcemia
of the nephrotic
patients
and demonstrate
that
secondary
hyperparathyroidism
may develop
in patients
with nephrotic
syndrome
and normal
renal function.
Malluche
et a!. (43) found
that
patients
with nephrotic
syndrome
and normal
renal
function
had
overt
histological
findings
of
osteomalacia
and enhanced
bone
resorption
reflecting
the state
of vitamin
D deficiency
and that of secondary
hyperparathyroidism.

Data on morphometric
evaluation
of biopsies
on patients
with nephrotic
syndrome
renal

C
0
0
0

c%J

a-

0
0

-I

600

z
wE

400

a.
200
0
0
5

0
PROTEIN

FIG.

5. The

10
IN URINE

IS

-J

g/24hrs

effects
of changes
in the degree
of proteinuria on blood
levels of 25-hydroxyvitamin
D in five
patients
with
nephrotic
syndrome.
Open symbols
represent patients
in whom
the decrease
in proteinuria
occurred
with steroid
treatment,
and closed
symbols
denote
patients
with
spontaneous
improvement
in the proteinuria. From Goldstein
et ah. (25).

_7f

BLOOD

IONIZED
CALCIUM
mg/IOOmI

FIG.
6. The relationship
between
the blood
levels of
ionized
calcium
and amino-terminal
fragment
of parathyroid
hormone
in 7 patients
with nephrotic
syndrome
and normal
renal
function.
From
Goldstein
et al. (25).

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

the importance
of the duration
of the proteinuria. Furthermore,
Goldstein
et al. (25) have
demonstrated,
as mentioned
above,
an inverse relationship
between
the blood levels of
250HD3
and the degree
of proteinuria.
The
effect
of the improvement
in proteinuria
on
the blood levels of 250HD3
was also studied
by Goldstein
et a!. (25). In five patients
in
whom the proteinuria
decreased
from 6.5
1.1 to 0.7 0.3/24
hr either
spontaneously
or
after
treatment
with
glucocorticoids,
the
blood levels of 250HD3
returned
toward normal (Fig. 5). The change
in the blood levels
of 250HD3
followed
rapidly
the decrease
in
the proteinuria
and
in two patients
the
changes
in these parameters
occurred
within

patients
with
physiological

CALCIUM
TABLE

METABOLISM

Creatinine
ance

clear-

25-HCC

calcium

1.0

8.06

0.24

3.9 1.1

7.73

0.38

30 5

10.3

8.19 0.31

306

24.8

9.78

pg/mi

8.6

111 11

Goldstein

Ionized
mg/I

1.0

3.2

that

nephrotic

urinary

calcium

patients

to evaluate

cretion
of sodium
for the regression

value similar
cium deficient
fluid volume

is very

whether

excrelow (25).

this

Figure
of the

and calcium
correlation

with
of

(44, 45). In the

for the correlation

a slope
one or

0.08

2.6

3.72

0.16

1.9 0.2

9.5

3.69 0.10

2.9 1.2

5.5 0.9

4.02

3.7

0.5

g/IIXJ

0.08

ml

g/24

0.2

hr

6.5 0.8

0.1

1.6

0.1

and/or

the state

hyperparathyroidism.

8 depicts

a schematic

mechanisms

pathogenesis
of the
tabolism
in patients
These patients
may
longed
proteinuria,
25OHD3
in urine

presentation
involved

in the

disorders
of calcium
mewith nephrotic
syndrome.
display
marked
and prowhich will cause loss of
and, hence,
a fall in the

#{149}

-XIOO
CCr

2
I

Y.61X+.23

I
1,1

#{149}
#{149}
<ir..79
#{149}

I
I

CNO
-

Ccr

FIG.
cretion

7. The
of calcium

relationship

nephrotic
pawas 0.61, a

to that (0.57) observed

in caldogs undergoing
extracellular
expansion
(46). These observa-

to the hypocalcemia

possible

3.70

#{149} #{149}

hypo-

tions
indicate
that
nephrotic
patients
had
strong
calcium
retaining
forces,
and that the
hypocalciuria
could
not be entirely
explained
by the alterations
in the renal
handling
of
sodium
in those
patients.
The nature
of this
calcium
retention
is not clear but may be
of secondary

Proteinuria

calciuria
is related
to sodium
retention,
we
studied
the relationship
between
calcium
and
sodium
clearance
during
the administration
offurosemide
(Fig. 7). Under
normal
circumstances,
furosemide
increases
the urinary
cx-

slightly
greater
tient the slope

albumin

et al. (21).

We also found
in our

Serum

IXI ml

0.17

are not available.

It is possible
that the
of 250HD3,
in such
patients
may
bone
disease
and alter various
comof renal osteodystrophy.

In an effort

calcium

between

X 00

the

fractional

cx-

(xl00
\Ccr
and

sodium

(xl00
t\ Ccr
in 24 patients
with nephrotic
data
points were obtained
rosemide.
From
Goldstein

blood
that

levels
a decrease

of this

syndrome.
Thirteen
during
administration
et al. (25).

metabolite.

in the blood

of these
of fu-

It is possible
levels

of 250HD3

below 10.0 ng/m! will also be associated

with
a decrease
in the blood levels of l,25(OH)2D3.
A deficiency
of25OHD3
and/or
1,25(OH)2D3
may

cause

defective

intestinal

absorption

of

calcium
and impaired
calcemic
response
to
PTH. Indeed,
preliminary
data from our laboratory
indicate
that these two abnormalities
do exist in patients
with nephrotic
syndrome

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

From

Total

mi/mm

related

1577

and ionized
calcium
protein
excretion
and in those with
proteinuriaa

52 9

All nephrotics
n = 26
Nephrotics
Normal
renal
function
n=7
Nephrotics
Renal
failure
n = 19
Renalfailure
No proteinuria
n= 11

tion

SYNDROME

The blood
levels
of 25-HCC,
total
and albumin
and the 24-hr
urinary
in patients
with nephrotic
syndrome
renal
failure
but without
significant

failure
losses
worsen
ponents

IN NEPHROTIC

MASSRY

1578

AND

GOLDSTEIN
NEPHROTIC

Prote

_____

2JHCC

inuri

1,25

SYNDROME

(OH)2

Sodium

CC

Intestinal

Ca

______

absorption

resistence
to

PTH

Hicalcemia

__________________

PTH

Bone

osteomalacia
FIG.
8.
the nephrotic

Schematic
syndrome.

presentation

of the

hyperparathyroidism

_______________________

resorption
pathogenesis

and normal
renal function.
As a consequence
of the decrease
in intestinal
absorption
calcium
and
the skeletal
resistance
to

ca!cemic

action

to PTH,

true

ensues.
The latter
will stimulate
roid glands
and raise the blood

which

in turn

will enhance

the parathylevels of PTH

resorption.

Deficiency
of 250HD3
and/or
1,25(OH)2D3
may
also be associated
with defective
mineralization
resulting
in osteomalacia.
Sodium
retention,
hypocalcemia
and
secondary
hyperparathyroidism
may
all contribute
to
the genesis
of the hypocalcemia
in patients
with nephrotic
syndrome.
U
The authors
wish to thank
Grace
Fick,
and Mrs. Alice
tarial
assistance.

Mrs. Jamie
Mcomjean

Jimenez,
for their

disturbances

the

of
the

hypocalcemia

bone

Hypocalciuria
of the

Mrs.
secre-

References
1. DENIS,
W., AND S. HossoN.
A study
of the inorganic
constituents
of the blood
serum
in nephritis.
J. Biol.
Chem.
55: 183, 1923.
2. SALVESEN,
H. A., AND G. C. LINDER.
Observations
on the inorganic
bases and phosphates
in relation
to

protein

in calcium

ofblood

in patients

homeostasis

and

other

body

fluids

with

in Brights

disease
and in heart
failure.
J. Biol. Chem.
58: 617,
1924.
3. DAvIDsoN,
J. R. A. A case of adolescent
myxoedema,
accompanied
by nephrosis
and by tetany
of
parathyroid
origin,
treated
with thyroid
and Collips
parathyroid
extract.
Canad.
Med.
Assoc.
J. 15: 803,
1925.
4. BOYD,
G. L., A. M. COURTNEY
AND
I. F.
MACLACHLAN.
The metabolism
of salts in nephritis.
I. Calcium
and phosphorus.
Am. J. Diseases
Children 32: 29, 1926.
5. Lw,
S. H. The
partition
of serum
calcium
into
diffusible
and
nondiffusible
portions.
Proc.
Soc.
Exptl.
Biol. Med.
24: 817, 1926.
6. SCRIvER,
WDEM.
Observations
on the excretion
of
calcium
in two cases of nephrosis
treated
with parathyroid
extract.
J. Clin.
Invest.
6: 115, 1928.
7. EMERSON,
K., AND W. W. BECKMAN.
Calcium
metabolism
in children
with nephrosis.
I. A Description
of an abnormality
in calcium
metabolism
in children
with nephrosis.
J. Chin. Invest.
24: 564, 1945.
8. GOTrFR1ED,
S. P., J. F. STEINMAN
AND B. KRAMER.
Chemical
studies
in children
with the nephrotic
syndrome.
Am. J. Diseases
Children
74: 283, 1947.
9. KEITH,
N. K., M. H. POWER,
G. W. DAUGHERTY
AND
H. M. KEITH.
Some
effects
of cortisone
on
metabolic
disturbance
associated
with
renal
edema.
Arch.
Internal
Med.
89: 689, 1952.
10. METCOFF,
J., C. P. RANCE,
W. M. KELSEY,
N.

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

Secofdary

retention

CALCIUM
KAKASONE

C. A.

AND

trophic

hormone

METABOLISM

JANEWAY.

(ACTH)

IN NEPHROTIC

Adrenocortico-

therapy

of the

osteomalacia.

nephrotic

28.

syndrome

in children.
Pediatrics
10: 543, 1952.
1 1. MCLEAN,
F. C., AND A. B. HASTINGS.
The state of
calcium
in the fluids
of the body.
I. The condition
affecting
the ionization
of calcium.
J. Biol. Chem.
108: 285, 1955.
12. TEGELAERS,
W. H., AND H. W. TIDDENS.
Changes
in electrolyte
metabolism
during
remission
of nephrosis.
Helv.
Paediat.
Acta
10: 269, 1955.
13. STANSBURY,
S. W., AND D. MACAULAY.
Defects
of
renal
tubular
function
in the nephrotic
syndrome.
Quart.
J. Med.
26: 7, 1957.
14. DANOWSKI,
T. S., F. A. WEIGAND,
L. GREENMAN,
S. GAILANI,
W. V. GREENBERG
AND F. M. MATEER.
Corticotropin
(ACTH)
therapy
of nephrotic
syndrome
in children.
Am. J. Diseases
Children
93: 604,
1957.

15.

plexed,

and

plasma.

Quart.

HOOFT,

18.

P.

BORDIER.

the

Acta

of

15: 437,

22.

24.

25.

26.

calcium

CHIO

in

AND

35.

C.

ALEVIZAKI

calcium

absorption

Internal

Med. 86:
B., AND

NORDIN,

I.

Urinary

AND

D.

IKKOS.

in the nephrotic
746, 1977.

36.

37.

38.

R.
excretion

FRASER.
data

for

calcium
recognition

ions

124:

302,

PARLIER.

in chronic
1969.

Calcium

KLEEMAN.

J. W., M. H.
MASSRY.

renal
et mala-

Divalent

ion

A. S.

KOPPEL,

Study

excre-

of

intestinal

BRICKMAN
absorption

calcium

J. G.,

HADDAD,

J. G.,

HADDAD,

J.

AND

Y., K.

NISHII,

M.

WALGATE.

in human

plasma.

J.

WALGATE.

AND

noassay
of the binding
metabolites
in human
1217, 1976.

protein
serum.

25-Hydroxyvi-

J. Biol.

Chem.

Radioimmu-

for vitamin
J. Cliii.

D and its
Invest.
58:

M. FUKUSHIMA,
T. SHIMR. NIKI, I. MATSUNAGA,
S. SASKI AND T. SUDA. Me25-hydroxyvitamin
D3 and Ia-hydroxyKUMAKI,

ON0,
H. OKAWA,
OCHI,
Y. TOHIRA,

tabolism

ne-

of

vitamin

D3 in experimental
rats with chronic
renal
failure.
In Vitamin
D: Biochemical,
Chemical
and
Clinical
Aspects
Related
to Calcium
Metabolism,
edited
by A. W. Norman,
K. Schaefer,
J. W. Coburn,
H. F. DeLuca,
D. Fraser,
H. G. Grigoleit
and D.
Herrath.
Berlin: Walter
de Gruyter,
1977, pp.
179-181.

41.

T. J., B. A.

HAHN,

C. R.

HENDIN,

SCHARP

G. HADDAD.
Effect
of chronic
anticonvulsant
apy on serum
25-hydroxycalciferol
levels
New Engl.
J. Med.
287: 900, 1972.

42.

of

Am.

in patients
with
renal
failure.
Kidney
Internat.
3: 264, 1973.
MASSRY,
S. G., AND J. W. COBURN.
Divalent
ion
metabolism
and renal
osteodystrophy.
In: Clinical
Aspects
of Uremia
and
Dialysis,
edited
by S. G.
Massry
and
A. L. Sellers.
Springfield:
Charles
C
Thomas,
1976, pp. 304-387.
MASSRY,
S. G., J. W. COBURN,
D. B. N. LEE, J.
JOWSEY
AND C. R. KLEEMAN.
Skeletal
resistance
to
parathyroid
hormone
in renal
failure:
study
in 105
human
subjects.
Ann.
Internal
Med.
78: 357, 1973.

K.

infusion

R.

M.
C. R.

AND

S. G.

R.,

GREENLAw,
HAHN,

reab-

nephron.

de lOs. Tone
III. Rein
et metaba letat pathologique.
Paris, ExpanFrancaise,
1965, p. 196.
M., L. I. SCHAINUCK,
S. G.

tamin
D transport
251:4803,
1976.
39.

Med.

AND

Scientifique

COBURN,

IZU,

Ann.

dog

in

tion in chronic
kidney
disease.
Relation
to degree
of
renal
insufficiency.
Clin.
Sci. 38: 297, 1970.
OGG, S. The intestinal
absorption
of47Ca
by patients
in chronic
renal
failure.
Chin. Sci. 34: 467, 1968.

of

Intestinal

syndrome.

A.,

POPOVTZER,

AND

40.

phrotic syndrome.
Lancet 2: 105, 1977.
LIM, P., E. JACOB,
E. P. C. TOCK AND H. S. PINEE.
Calcium
and phosphorus
metabolism
in
nephrotic
syndrome.
Quart.
J. Med. 46: 327, 1977.
GOLDSTEIN,
D. A., Y. ODA, K. KUROKAWA
AND S.
G. MASSRY.
Blood levels of 25-hydroxyvitamin
D
in patients
with
nephrotic
syndrome.
Ann.
Internal
Med.
87: 664, 1977.
MOUNTOKALAKIS,
T., C. VIRVIDAKIS,
P. SINGH.

ofthe

of divalent

Internal

LICHTWITZ,

MASSRY

PINEE.

syndrome.

handling

Arch.

sions

J. A.

H. S.

nephrotic

renal

metaboliques
olism
du calcium

34.

26: 75,

AND

and

S. G., J. W. COBURN,
L. W. CHAPMAN
C. R. KLEEMAN.
Effect
of NaC1
infusion
on
urinary
Ca
and Mg
during
reduction
in their
filtered loads. Am. J. Physiol.
213: 1218, 1967.
COBURN,
J. W., M. M. POPOVTZER,
S. G. MASSRY
AND
C. R. KLEEMAN.
The physiocochemical
state

dies

AND

Med. 45: 421, 1976.

SCHMIDT-GAYK,
H., W. SCHMITT,
C. GRAWUNDER,
E. RITZ,
W. TSCHOPE,
V. PIETSCH,
K. ANDRASSY
AND
R. BOUILLON.
25-Hydroxyvitamin-D
in

test.

32.

J.

ELLAKIS,

27.

Pediatrics

azotemia

observa-

unmineralized
bone
intestinal
malabsorption

MASSRY,

failure.

complicat-

ROSEVEAR

and

J. Pathol. Bacteriol. 9: 545, 1966.

C. G., AND J. F. WATSON.
Calcium

DUARTE,

and

Helv.

POWER

dysfunction

Med. 36: 301, 1967.

LIM,
P., E. JACOB,
L. F.
ionized

31.

revela-

1960.
ULRICH.
Renal
tubular
dysfunction
complicating
the
nephrotic
syndrome:
the disturbance
of calcium
and
phosphorus
metabolism.
Proc.
Mayo
Chin. 37: 376,
1962.
JONES,
J. H., D. K. PETERS,
D. B. MORGAN,
G. A.
COVES
AND N. P. MALLIK.
Observations
on calcium
metabolism
in the nephroric
syndrome.
Quart.
J.

G. B., J. W.

STICKLER,

Serum
Quart.

23.

M. H.

HAYLES,

1956.
Quantitative

AND

1960.

G. B., A. B.

STICKLER,

30.

de-

therapy.

renal

823,

BALL.

sorption
in proximal
tubule
J. Physiol.
212: 1355, 1967.

33.

stigmate

J.

AND

mineralized

syndrome.

29.

in

Metaphyseal

on

chronic

com-

calcium

1958.

hormone

J. A. ULRICH.
Renal
tubular
ing the nephrotic
syndrome.

21.

ionized,
of

Lhypocalciurie

introduction

Paediat.

20.

The

fractions

teur de linsuffisance
glomerulaire.
Presse
Med.
68:
167, 1960.
Hoorr,
C., A. VERMASSEN
AND M. VAN BELLE.
On
calcaemia
and phosphataemia
in the nephrotic
syndrome.
Comparative
study
of the periods
before
and
after

19.

ROSE.

of the bone in nephrosis,

with reference
Ann.
Paediat.
(Basel)
191: 129, 1958.
A., S. DESEZE,
R. PARLIER,
D. HioCo

LICHTWITZ,
AND

G. A.

J. Med. 27: 463,

C., AND A. VERMASSEN.

calcification
to its origin.
17.

AND

proteinbound

tions

270:

Lancet

A.,

GARNER,

1579

from
Cliii.

J.

HADDAD

anticonvulsant
Res. 20: 56,

J.

PRYOE,
AND

drugs:

1972.

C.

J.
ANAST.

therpeutic

J.

AND

therin adults.

WINNACKER,
Osteomalacia

implications.

T.

Downloaded from ajcn.nutrition.org by guest on March 31, 2013

16.

A.,

FANCONI,

SYNDROME

MASSRY

1580
43.

44.

MASSRY.

Bone

out

failure.

renal

ANTONIOU,
AND

dium
Cliii.
45.

H.

MALLUCHE,

L. S.
and

Med.

EKNOYAN

H.,
disease

Cliii.

D.

A.

L. D., G. M.
LILIENFIELD.

calcium
74: 410,

G., W.

GOLDSTEIN

AND

in nephrotic
syndrome
Res. 26: 129A,
1978.
EISNER,
Relationship

L. A.

AND

GOLDSTEIN

S. G.

SLOTKOFF

between

so-

transport
in the kidney.
J. Lab.
1969.
N. SUKI AND M. MARTINEZ-MAL-

Effect
of diuretics
on urinary
excretion
of
phosphate,
calcium,
and magnesium
in thyroparathyroidectomized
dogs. J. Lab. Cliii. Med. 76: 257,
1970.
BRICKMAN,
A. S., S. G. MASSRY
AND
J. W. CoBURN.
Calcium
deprivation
and renal
handling
of
calcium
during
repeated
saline
infusions.
Am.
J.
Physiol.
220: 44, 1971.
DONADO.

with-

46.

Downloaded from ajcn.nutrition.org by guest on March 31, 2013