original
Variability of creatinine excretion phenylketonuric and galactosemic children treated with anticonvulsant Jane
S. Lewis,3
Dr.P.H.,
Mary
ABSTRACT
300-500% significantly
Louise
Bunker,4
Creatinine
of more
the
per minute
24-hour variable
Sue S. Getts,
value for
excretion for
of normal, children, and drugs”2
M.A.,
and Ruth
Essien,
rates in individual
several
children
communications
children.
treated
with
voidings
Creatinine
M.A.
varied
as much
excretion
anticonvulsant
drugs
rates
than
for
as
were normal
children. Riboflavin-creatinine ratios determined on individual voidings were variable but adequate although total riboflavin was low. No time of day was found when creatinine excretion was representative of the 24-hour value. The creatinine height index when calculated from timed individual voidings during a 24-hour period varied for some children from 0.5 to more than 1.5 times published norms. Am. J. Clin. Nutr. 28: 3 10-315, 1975
Because creatinine excretion was believed to be constant for an individual it has been used as an index for urinary metabolites. However, recently several investigators found creatinine excretions of individuals were variable from one voiding to the next of adults (1-6), adolescents (7), and a few children (8, 9). Because 24-hour urine collections are difficult to obtain for children this study was made to determine if there is a time of day that a timed voiding is representative of the 24-hour creatinine excretion of a child so that it can be used for calculation of metabolite-creatinine ratios or creatinine height index.
individual
voidings
children. for the collection.
and
The subjects were S phenylketonuric, 7 galactosemic children, and 10 children receiving anticonvulsant drugs (dilantin combined with some other drug), all attending clinics at Childrens Hospital, Los Angeles, and 28 normal children, children of nutrition students
or
their
310
The American
Journal
of Clinical
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were
calculated
for
29
was calculated 24-hour urine
Findings
As
shown
in of
Table
variation
1
the
mean
of
the
children
of
the being
with
anticonvulsant drugs was signifi(P < 0.01) than the mean of the coefficients of variation of the normal children. Some children, as shown in Fig. 1, had creatinine per minute excretion rates for individual voidings that were 300-500% of the cantly
friends.
Urine, as spontaneously voided by each child during a 24-hour period, was timed, and each voiding preserved in separate brown bottles with 3 ml glacial acetic acid/i 00 ml urine, covered with toluene, and frozen until analyzed by alkaline picrate method for creatinine (10) and the Slater-Morell method for riboflavin (11). The creatinine excreted per minute for each voiding and the mean value of creatinine per minute in the
day
of variation each child’s
height index was calculated for all 50 using the creatinine values for normal children and Alvarado (13) and Clark et al. (14).
creatinine children of Viteri
treated
methods
the
Riboflavin in individual contiguous voidings of 6 children was determined and riboflavin-creatinine ratios were calculated and compared to the criteria of the Ten State Nutrition Survey (12). For each of 21 children the voidings were pooled and creatinine determined for the 24-hour period. The
coefficients
Subjects
for
The coefficient voidings in
higher
24-hour
made
value.
‘From California 2
in
Annual
3Professor, 4Graduate 28:
excretion
(which
APRIL
State
part
at
Meetings,
Home student. 1975,
rate
is the
the California 90032.
Presented
Nutrition
Nutrition
The
on rising
of the
University,
the
and
Economics
pp. 310-315.
of the
Los Angeles,
American
1972
voiding
last voiding
Institute
of
1973.
Department.
Printed
in U.S.A.
VARIABILITY
TABLE
OF
CREATININE
311
EXCRETION
1
Coefficient of variation” of creatinine per minute in timed voidings of normal, galactosemic and phenylketonuric children, and children being treated with anticonvulsant drugs
Sex Ages,
years
Mean
SD
N
M
F
14
8
6
2-10
27.2
±
15.7
7 8
S 7
2 1
3-9 4-10
34.6 54.3”
±
7.6 24.0
±
Range
% Normals PKUGalactosemicb Dilantin treated
SD of mean “Coefficient
of variation
Phenylketonuric
b
=
mean 1 phenylketonuric
males,
±
% 3-73 23-48 16-103
100.
X
female,
1 galactosemic
male,
and
1 galactosemic
female.
cP
0
Or,
Cl,
4 puns
2
-
0.22
Or
-
0.13
10
#{128}
.1?,
pumns
0.96
Cr
Or0.60g
4.0
6..
2.0
2.0
1.0
1.0
1
ratios acceptable
0.21
0.23
ag 6
3.8
3.0
FIG. 2. Riboflavin-creatinine dotted line represents the Nutrition Survey (12).
3 ys..rs -
ug
S.
in contiguous riboflavin-creatinine
(12) in midmorning and midafternoon, and the only unacceptable ratios for them were in the early morning voidings (the last voiding in the 24-hour collection). These children had very low creatinine excretions which resulted in high vitamin-creatinine ratios. Figure 3 shows that for these children the highest rates of riboflavin excreted per minute did not occur with the highest rates of creatinine excreted or vice versa. If the timed voiding with the lowest creatinine per minute excretion had been used to calculate the creatinine height index, 27 of the 29 children would have had creatinine height indexes below 0.9, as shown in Fig. 4. If the highest creatinine rate had been used 21 of 29 children would have had creatinine height indexes above 1.0. Subjects DL, ML, JA, and DF had creatinine height indexes based on 24-hour collections that were 50% or less than published norms (13) yet they had individual voidings which if the creatinine were extrapolated to 24 hours would have given creatinine height indexes of 1.3-1.8.
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8,30..
7S5
voidings
a 24-hour period for 6 children. according to the criteria of the Ten
during
ratio
Only height normal Fig. 5. 0.8 but shown
7 out of 50 children had indexes that were equal to or values of Viteri and Alvarado The mean creatinine height the mean relative weight was in Table 2.
The State
creatinine above the (13). See index was normal as
Discussion As observed by other investigators (1-9) creatinine excretions of individuals were variable during a 24-hour period. Schizophrenics (15, 16) and mental patients during emotional changes (17) were observed to have greater changes in creatinine excretion just as the children being treated for seizures had more variable excretions. Variability in metabolite-creatinine ratios was also observed by Hegsted et al. (18), Kulkarni and Kilgore (9), and Clark et al. (7) who likewise found that riboflavin-creatinine and thiamin-creatinine ratios sometimes were acceptable
midafternoon or unacceptable
or
high
voidings in
in
the
midmorning
and
when they had been low the first voiding in the
VARIABILITY
OF
CREATININE
EXCRETION
313
Oj
CREATININE RIBOFLAVIN
‘.5
+---
0.10
0.0
ID
-
-
-
DP 0
I
7:30am
7:30pm
7:30am
z
O.5L&J
z z
I-, 4
w U
:00am
6:00pm
6.-OOc
m
I3X
1.5
I.0
0-I
(-I
Jp
8:OOum FIG. 24-hour
aoOpm
3. Riboflavin per minute period for 6 children.
and
800am creatinine
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per
minute
excretion
rates
in
contiguous
voidings
during
a
LEWIS
314
ET
morning. Thus at times when specimens are likely to be collected in the field vitamincreatinine ratios may be considered acceptable when the 24-hour value is unsatisfactory. Prinsloo et al. (19) also found normal vitamincreatinine ratios when N-methylnicotinamide and creatinine lagrous children.
excretions height
study
Viteri
and
low
for
creatinine values may not be representative for heights of this generation of American children. Viteri et al. (22) checked the creatinine height index values by using 3-hour specimens of normal Guatemalan children. If urine specimens
pel0
Creatinine
in this
were
AL.
were
indexes
for
normal
lower
than
the
Alvarado
(13)
who
000
children criteria of
based
NORMAL
X
DILANTIN TREATED GALACTOSEMIC-PKU VITERIS
-
NORMALS
(25)
900
their
normal values on creatinine values of Stearns et al. (20) and the heights of Stuart and Stevenson (21) obtained a generation ago. Possibly these
Boo
0
0
600 z
0 500 (.2
0 401
x
300
x
0 20(
x 0
00
0 Jo
IOINAL
M%5LMJN$SJLSS duNN s 161108 AITO5VULSAII MUGS
CNILN5II
MC%CTIOUJPAL PSE5TIILTS.IIC 150 GALACTGSLNIC CN(LOINI
00
00
k.0)
FIG. normal,
5. Twenty-four-hour
phenylketonuric children being
and
treated
plotted
against height, creatinine excretions and
Alvarado
height
indexa children,
and and
mean relative weights’ children being treated
Creatinine
height
F
mean
All Normals
50 28
31 17
18 11
0.80 0.81
Dilantin treated Phenylketonuricgalactosemic”
10 12
9 6
1 6
0.79 0.79
creatinine excretion of and galactosemic children, with anticonvulsant drugs a curve representing normal height published by Viteri
of normal, galactosemic with anticonvulsant drugs
index
SD
±
Relative
range
height
index
weight
M
F
mean
SD
16 9
0.96 0.93
± ±
0.13 0.11
0.71-1.26 0.71-1.20
±
range
0.20-1.50 0.47-1.47
48 26
32 17
±
0.39
0.20-1.50
1
0.97
±
0.17
0.78-1.26
0.26
0.40-1.32
10 12
9
±
6
6
0.97
±
0.15
0.81
24-hour
creatinine
=
=
males,
N
0.27 0.22
±
creatinine
subject. 50th
Phenylketonuric
weight
±
subject’s
4
40
sex
M
24-hour
C
.20
(13).
sex N
b Relative
and for
11U
CM
2
Mean creatinine and phenylketonuric
#{176} Creatinine
‘0
HEBKI
FIG. 4. Creatinine height index based on 24-hour excretion (o) and range of values (I.-, -.j,) for creatinine height index calculated from - individual voidings during the same 24-hour period for normal, phenylketonuric and galactosemic children, and children being treated with anticonvulsant drugs.
TABLE
0
percentile
weight
1 phenylketonuric
of normal
children
same
height
and sex
weight for
subject’s
female,
Downloaded from https://academic.oup.com/ajcn/article-abstract/28/4/310/4716480 by University of Glasgow user on 26 April 2018
height
and
2 galactosemic
sex males,
and 5 galactosemic
females.
-1.14
VARIABILITY
were rates
collected midday creatinine might have been higher than
the
OF
CREATININE
modification determining
excretion 24-hour
rate.
Since a
creatinine
subject,
excretion
nor
depressed
is
at
it
a given
is not
constant
consistently
elevated
time
there
of day,
for
creatinine
excretion
said
that
rate.
creatinine
give
erroneous
not
be used
as a reference
that
24-hour
urine
reliable
results
estimates
We
used (6,
with that
standard
may
(24),
would
urinary
others 14.
it should give
metabolites
and more (19).
15.
El References 1. CURTIS, G., AND M. FOGEL. Creatinine excretion: diurnal variation and variability of whole and part-day measures. Psychosom. Res. 32: 337, 1970. 2. RUBIN, R. T. Urine creatinine excretion: variability and volume dependency during sleep deprivation. Psychosom. Med. 33: 539, 1971. 3.
PASTERNACK, nal variations
creatinine. 1971. 4.
S.
A., AND B. KUHLBACK. Diurof serum and urine creatine and Scand. J. Clin. Lab. Invest. 27: 1,
6. VESTERGAARD, P., AND R. LEVERETT. Constancy of urinary creatinine excretion. J. Lab. Clin. Med. 51: 211, 1958. 7. CLARKE, R. P., L. DE G. COSGROVE AND E. H. MORSE. Vitamin to creatinine ratios. Am. J. Clin. Nutr. 19: 335, 1966. 8. RAM, M. M., AND V. REDDY. Variability in urinary creatinine. Lancet 2: 674, 1970. 9.
KULKARNI, variations
Nutrition
16.
17.
M.,
AND
L.
KILGORE.
of hydroxyproline and creatinine tion in children. Am. J. Clin. Nutr. 26: 1973.
ODDS. normal women.
10.
Interdepartmental
11.
National Defense (ICNND). Manual for Nutrition Surveys. Bethesda: National Institutes of Health. 1963, p. 135, p. 246. SLATER, E. C., AND D. B. MORELL. A
Committee
on
Nutrition
Downloaded from https://academic.oup.com/ajcn/article-abstract/28/4/310/4716480 by University of Glasgow user on 26 April 2018
Education
Survey
Atlanta,Ga.:
and
method of materials. Welfare.
1968-1970, Center
Ten BioControl,
IV.
for Disease
The variability of creatinine subjects, mental patients
excretion and pregnant
Chin. Chim. Acta 26: 567, 1969. D. M., S. N. GERSHOFF,
18. HEGSTED,
19.
20.
21.
AND
D.
H.
JOLLY.
22.
23.
for
24.
M.
Variation
in
F. in
riboflavin excretion. J. Nutr. 60: 581, 1956. PRINSLOO, J. G., J. P. DU PLESSIS, H. KRUGER, D. J. DE LANGE AND L. S. DE VILLIERS. Protein nutrition status in childhood pellagra. Evaluation of nicotinic acid status and creatinine excretion. Am. J. Clin. Nutr. 21: 98, 1968. STEARNS, G., K. J. NEWMAN, J. G. McKINLEY AND P. C. JEANS. The protein requirements of children from one to ten years of age. Ann. N. Y. Acad. Sci. 69: 857, 1958. STUART,
H.
C.,
AND
S.
S.
Physical growth and development. of Pediatrics (6th ed.), edited by
Diurnal
excre1069,
fluorimetric in biological 1946.
DHEW Pub!. No. (HSM) 72-8132, 1972, p. 224. VITERI, F. D., AND J. ALVARADO. The creatinine height index: its use in the estimation of the degree of protein depletion and repletion in protein calorie malnourished children. Pediatrics 46: 696, 1970. CLARK, L. C., H. L. THOMPSON, F. I. BECK AND W. JACOBSON. Excretion of creatine and creatinine by children. Am. J. Diseases Children 81: 774, 1951. SVED, S., A. PERALES AND J. P. HOULE. Urinary creatinine in drug excretion studies in chronic schizophrenics. Brit. J. Psychiatry 120: 219, 1972. PSCHEIDT, G. R., H. H. BERLET, J. SPAIDE AND H. E. HIMWICH. Variations of urinary creatinine and its correlation to excretion of indole metabolites in mental patients. Clin. Chim. Acta 13: 228, 1966. CHATTAWAY, F. W., R. P. HULLIN AND F. C.
TRULSON
PLOUGH, I. C., AND C. F. CONSOLAZIO. The use of casual urine specimens in evaluation of thiamine, riboflavin and N’ -methylinicotinamide. J. Nutr. 69: 365, 1959. LIS, A. S., D. I. McLAUGHLIN, R. K. McLAUGHLIN AND K. F. DE HACKBEIL. The function of creatinine: nocturnal-diurnal variation. Physiol. Chem. Physics 4: 70, 1972.
of the riboflavin
chemical.
13.
315
Biochem. J. 40: 644, U.S. Dept. Health,
State
or
as an index
7, 23),
collections of
agree
12.
is no
period during the day that a urine specimen can be assumed to be representative of the 24-hour
who
EXCRETION
Philadelphia: VITERI,
Saunders, 1954, E., J. ALVARADO
STEVENSON.
In: Textbook
W. p. 10-66.
E.
Nelson.
F. AND G. A. 0. ALLEYNE. Reply to Drs. Mendez and Buskirk. Am. J. Clin. Nutr. 24: 385, 1971. POLLACK, H. Creatinine excretion as an index for estimating urinary excretion of micronutrients or their metabolic end products. Am. J. Chin. Nutr. 23: 865, 1970. PATERSON, N. Relative constancy of 24 hour urine volume and 24 hour creatinine output. Clin. Chim. Acta 18: 57, 1967.