Otto

Mehls,2

Eberhard

Ritz,3

Giulio

ABSTRACT been

Acceleration

demonstrated

Clinical

by

improvement

rats

(subtotal

animals

animals

growth

rate

animals. vitamin

were

D. Since

D-treated actions

with greater

uremic to the of

growth.

vitamin Am.

and

vitamin in

intake

with

Both

animals,

the effects Nuir.

Journal

ofClinical

Nutrition

and

with

may

D.

be associated

31: 1927-1931,

3 1: OCTOBER

and

on food

D

growth

were

vitamin

controls zone

than

intake

rate

under

study

with

or causally

perhaps

study

lesions. associated

in which

uremic

were

compared

supplementation.

In

signficantly in the

rats

uremic

This

D has

of skeletal

related

D

than cannot

imporant to the

in and

uremic

markedly

animals

vitamin

than gain

corresponding

were

demonstrates

weight

with uremic

greater

D supplements,

of uremic

D-treated

in growth

of vitamin

of vitamin

to healing

vitamin

and without

in vitamin

administration

D supplementation

pair-fed

increase

after attributed

in an experimental

without gain

B. Krempien4

an effect

vitamin

in the growth

In children with chronic renal insufficiency, retardation of growth is commonly observed. Several factors have been implicated in its pathogenesis, such as, protein and calorie malnutrition, acidosis, renal osteodystrophy, and endocrine abnormalitie i.e., somatomedin deficiency, hyperdrenocorticism, and insulin resistance (1). Betts and Magrath (2) proposed that in children with chronic renal insufficiency “growth progresses steadily throughout childhood, but at a lower centile, until they develop renal rickets”. This is in agreement with the observation of West and Smith (3) that renal osteodystrophy is associated with cessation of growth. It has been shown that so called “renal rickets” is the consequence of an acquired resistance to vitamin D resulting from a disturbance in the metabolism of vitamin D (4). It is possible that the alterations in vitamin D metabolism affect growth long before changes in skeletal x-rays become noticeable. This notion is supported by an observation of Dent et al. (5). This author noted a resumption of growth with evidence of accelerated growth in children with renal osteodystrophy who were treated with vitamin D. Improvement in growth was associated with healing The American

without

sham-operated

skeletal J. Clin.

D has also be confirmed

was greater

D which

been

has

D, weight

diet.

abnormalities food

children

This

could rats

on the control

Histological

exclusively

with

and

of uremic

vitamin

control

supplemented

uremic

that This

nephrectomy) pair-fed

Wangdak,3

authors.

of vitality.

sham-operated

Tashi

of growth

various

suggest

observations

with

Gilli,2

in

reduced

by

in nonvitamin be attributed extraskeletal

improvement

of

1978.

of the bony lesions. But in one child studied (case 13) vitamin D was given although radiological evidence of rickets was not present, and in this child growth velocity also increased. An increase in growth subsequent to the administration ofvitamin D has also been noted by Royer et al. (6), Potter et al. (7) and ourselves (unpublished observations). These authors showed that linear growth was promoted in parallel with the healing of rickets. However, as correctly pointed out by Tiddens (8), it is impossible to accept a direct relationship between vitamin D treatment and the marked increase in the growth rate without data on calorie intake. This factor is difficult to control in clinical studies. Therefore, the present investigation was designed to study the effect of vitamin D on food intake, weight gain, longitudinal growth, and bone histology in nonvitamin D-depleted uremic rats. tThis work was supported schungsgemienschaft. 2 Universit#{228}ts-Kinderklinik,

by

the

Deutsche

Im

Neuenheimer

ForFeld

150, D-6900 Heidelberg, Federal Republic of Germany. 3 Medizinische Universit#{228}tsklinik, Bergheimerstr. 58, D-6900 Heidelberg, Federal Republic of Germany. 4 Pathologisches Institut der Universit#{228}t, Im Neuenheimer Feld 120, D-6900 Heidelberg, Federal Republic of Germany.

1978, pp.

1927-193

1 . Printed

in U.S.A.

1927

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Effect of vitamin D on growth 1 experimental uremia

MEHLS

I 928

Materials

and

Ivanovas, KisAfter arrival

to the diet and metabolic

cages

for I week. The animals received Altromin R (1000) (Fa. Altromin, Lage/Lippe) (Ca 0.95%; ; P 0.8%; vitamin D 1600 lU/kg; 3.3 kcal/g; protein 17.5%). The group with vitamin D therapy received the same diet to which vitamin D3 (Vigantol R/ Fa. Merck Darmstadt) had been added to a final concentration of 9600 lU/kg. The animals were exposed to a 12-hr on- 12-hr off-lighting cycle at constant temperature (24 C) and humidity (60%). After the adaptation period, the animals were subjected to two-stage subtotal (8/10) nephrectomy (subtotal resection and irradiation (400 rad) ofthe left kidney

length 39 without with

----

vlt.D vO.D

37

35

33 fed 31 rats

39

27

I

t

FIG.

TABLE

1 . Growth

rates

1

1l

in uremic

and

control

animals

Serum P

mEq/iizer

Without vitamin D supplement (I) Control ad libitum n = 12 Control pair-fed n = 13 Uremia n = 13

26days

containing

All values differences).

or lacking

vitamin

D.

40.2

± 0.26

± 2.7

4.39

6.8

54.3

814

±0.04 4.09

± 0.12

±6.46 348.3

± 45 137

14.96 ± 085b

±0.06

±

SEM.

between

47.5 ±3.2 30.2 ±4.3

1125b

29l.l’

1.02

±46.7

719 ±38 131b

± 17

Difference between uremia and I and II P < 0.05 (Wilcoxon test for b

Initial

27b

760b

6.97 ±0.19 7.34 ±0.12 ±

.

weight

Final

control random

Cumulative . food intake

weight

g

gal/min/I6WJg

7.7

4.71 ±0.11’ are given as ‘ Difference

Crcatinine clearance

4.18 ± 0.07a

4.59 ±0.llc 4.64

11

Urea mg/100m1

± 0.13

With vitamin D supplement (II) Control ad hibitum n= 12 Control pair-fed n= 11

a

diets

1

Ca

Uremia n=

20

fed

93.8 ± 2.4

198.1 ± 5.1

295

91.9

117.2

159.9

± 2.9 90.8 2.4

± 5.6

± 7.2

±

8.3

104.5

159.9

± 5.5

± 7.2

94.4 ±2.5 92.8 ±2.5 908?)

204.6

302 ±8.7 200.3 ± 8.8’

±2.44

±7.1’

P < 0.02 samples).

±4.6 158.6 ±5.2’ 1317b

(Wilcoxon

200.3 ± 8.8’

test

for paired

Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1927/4656062 by University of Rhode Island user on 08 December 2018

were adapted

rats, 50 g, (Fa. for the experiments.

AL.

followed after 1 week by resection of the contralateral right kidney) or sham operation, irradiation, and decapsulation of the kidney. Animals were matched on the basis of body weight. The uremic animals were given 20 g food at 7 PM; after 12 hr the remaining food was removed and weighed. On the following day, the corresponding control animals were given exactly the amount of food consumed by the uremic animals. Snout-tail length was measured in deep relaxation (ether anesthesia). The animals were killed after 24 days. Serum and urine chemistries were measured with a SMA-l2 Technicon autoanalyzer (9). Bone histology was studied on undecalcified sections of the tibia after embedding in methyhnetacrylate. The sections were stained after Masson-Goldner or after Krutsay and evaluated as described previously (9).

methods

Male Sprague-Dawley legg/Allg#{228}u) were used

the animals

ET

VITAMIN

D

IN

EXPERIMENTAL rd------

-

/

.

f

w:

:8

fI

. ‘

-



..,

S.

,‘.

...,

...

s

I

, rFIG. 2. Uremic animal, nonfortified diet (proximal x37). Zone ofgrowth cartilage (top), marked increase slender irregular trabecules with persisting chondrocyte

8



tibia, undecalcified in the width ofprimary “capsules”. Cortical

Results The degree of uremia in uremic animals with and without vitamin D supplementation was comparable as indicated by endogenous creatinine clearances. Under vitamin D, there was a moderate increase in serum Ca and no noticeable change in serum P levels. Animals treated with vitamin D grew faster (Fig. 1) and achieved higher final length and weight (Table 1). But cumulative intake of

-

--

i

section, v. Kossa stain, microphotograph spongiosa which consists of numerous bone exhibiting erosive defects.

food was also significantly higher in vitamin D treated as compared to nonvitamin Dtreated uremic rats. Pair-fed control animals grew better than the corresponding nonvitamin D or vitamin D-treated uremic animats, pointing to the higher energy cost of growth in uremia (10). In the growth zone of the upper tibia of uremic animals without vitamin D therapy (Fig. 2), irregularities of the growth cartilage, particularly in the zone of degenerative cartilage, were noted. There

Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1927/4656062 by University of Rhode Island user on 08 December 2018

ZI,”

_,.,

1929

UREMIA

193()

animals under vitamin D therapy. Vitamin D improved the histological abnormalities (rickets) in the growth zone and in metaphyseal bone. However, food intake was markedly higher in uremic animals with vitamin D. Consequently, it does not necessarily follow that the increase in longitudinal growth is exclusively due to a skeletal action of vitamin D. The increase in growth is the more remarkable since uremic animals given vitamin D were considerably more active than uremic

increase in the width of the zone of spongiosa which consisted of dense, irregularly formed spicules. The cxof osteoid seams on the trabecular was markedly increased. These abwere markedly reduced in uremic with vitamin D therapy (Fig. 3).

Discussion The growth

above results document velocity and weight

an increase of gain in uremic

‘i&__ ;

.

...,

,,.#

I’

.

! -

.‘

r’. ..-

_,#{149},

-

I ilS’-,.

FIG. 3. microphotograph longitudinally:

Uremic

animal, diet fortified with vitamin x40). Zone of primary spongiosa plump trajectorially oriented, secondary

D (proximal narrow; primary trabecules.

tibia, undecalcified section, v. trabecules regularly formed

Kossa stain, and aligned

Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1927/4656062 by University of Rhode Island user on 08 December 2018

was an primary slender, tension surface normalities animals

ET AL.

MEHLS

VITAMIN

D

IN

EXPERIMENTAL

References 1.

2.

3.

4.

5.

6.

7.

mats.

This

difference was not demonstrable in a study when older animals with lower growth rates and diets with lower calorie content were used (9). This observation suggests that the energy cost of growth is increased in uremia as previously proposed by Cantler et at. (10). The difference in growth rate (i.e., the difference in efficiency of utilization of food) was not abolished by vitamin D, i.e., uremic animals weighed less at the end of the experiment than pair-fed sham-operated controls that had received an identical amount of food. This indicates that the effect of vitamin D on growth does not result from increased efficiency of utilization of food. previous

8.

9.

10.

1 1.

12.

13. The authors thank Dr. H. Udes des Theoretikums, Im Neuenheimer for help and assistance.

(Versuchstiezentrale Feld, Heidelberg)

1931

14.

C., AND M. A. HOLLIDAY. Growth in children with renal disease with particular reference to the effects of calorie malnutrition: a review. Chin. Nephrol. 1: 238, 1973. BETTS, P. R., AND G. MAGRATH. Growth pattern and dietary intake of children with chronic renal insufficiency. Brit. Med. J. 2: 189, 1974. WEST, C. D., AND W. C. SMITH. An attempt to elucidate the cause of growth retardation in renal disease. Am. J. Disease Children 91: 460, 1965. DE LUCA, H. F. Recent advances in our understanding of the vitamin D endocrine system. J. Lab. Clin. Med 87: 7, 1976. DENT, C. E., C. HARPER AND 0. R. PHILPOT. The treatment of renal-glomerular osteodystrophy. Quart. J. Med. 30: 1, 1961. ROYER, P., H. MATHIEU AND S. GERBEAUX. Explorations biologiques du m#{233}tabolisme calcique chez l’enfant. In: Rein et Foie. Maladies de Ia Nutrition. Vittel: Symposium International sur la Lithiase Calcique, 1962. POTTER, D., D. LARSEN, E. LEUMANN, D. PERIN, J. SIMMONS, C. F. PIEL AND M. A. HOLLIDAY. Treatment of chronic uremia in childhood. II. Hemodialysis. Pediatrics 46: 678, 1970. TIDDENS, H. A. W. M. Growth limiting factors in renal disease. In: Somatic Growth of the Child, edited by J. J. van der Werfften Bosch and A. Haak. Leiden: 1966, p. 215. MEHLS, 0., E. RITZ, G. GILLI, H. SCHMIDT-GAYK, B. KREMPIEN, B. K0uRIST, H. WESCH AND P. GER. Skeletal changes and growth in experimental uremia. Nephron 18: 288, 1977. CHANTLER, C., E. LIEBERMAN AND M. A. HOLLIDAY. A rat model for the study ofgrowth failure in uremia. Pediat. Res. 8: 109, 1974. MATFHEWS, C., K. W. HEIMBERG, E. RITZ, B. AGOSTINI, J. FRITSCHE AND W. HASSELBACH. Effect of l,25-dihydroxycholecalciferol on impaired calcium transport by the sarcoplasmic reticulum in experimental uremia. Kidney Internat. 1 1 : 227, 1977. ARIEFF, A. I., AND S. G. MASSRY. Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis and parathyroid hormone. J. Chin. Invest. 53: 387, 1974. BETrS, P. R., AND R. H. R. WHITE. Growth potential and skeletal maturity in children with chronic renal insufficiency. Nephron 16: 325, 1976. HOLLIDAY, M. A. Calorie intake and growth in uremia. Kidney Internat. 2: 73, 1975. CHANTLER,

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animals not given vitamin D. It is unlikely that addition of vitamin D altered the palatability of the food, since nonuremic ad libitum fed animals failed to consume more vitamin D-supplemcntcd food. Vitamin D might increase longitudinal growth primarily by stimulating food intake. Such an increase in food intake could result from changes in serum calcium, muscle tone (1 1), or brain calcium (1 2) and from improvement in well being. Alternatively, the increase in food intake could merely result from the resumption of growth. Recent clinical observations (13) suggest that a change in energy intake of children with chronic renal insufficiency is a factor related to, but not a cause for, changes in growth velocity. The above measurements show that at a given intake offood (Le., calories and protein) uremic animals grow less than control ani-

UREMIA

Effect of vitamin D on growth in experimental uremia.

Otto Mehls,2 Eberhard Ritz,3 Giulio ABSTRACT been Acceleration demonstrated Clinical by improvement rats (subtotal animals animals grow...
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