Suppressive effect of 1α -hydroxyvitamin D3 on the hyperparathyroïdism of children on maintenance hemodialysis

Metab. Bone

Metabolic Bone Disease 8 Related Research

Dis. & Rel. Res. 1, 15-21 (19781

8 by S.N.P.M.D. (Paris 1978)

Suppressive of children

effect of 1 x -hydroxyvitamin on maintenance hemodialysis

SONIA BALSAN, MICHEL BROYER

JEAN

Laboratoire

fant

des

Tissus

GUERIS, Calcifiks

DAVID (C.N.R.S.

[I.N.S.E.R.M. U. 30). and Unit6

boiskre.

Paris,

Andre

LEVY,

MICHELE

Ds on the hyperparathyra”tism GARABEDlAN,

HUGUETTE

GUILLOZO,

AND

E.R. 1261, Unit6 de Recherches sur les Maladies du Mktabolisme chez /‘EnLichwitz (I.N.S.E.R.M. U. 18J, HGpital des Enfants Malades and HBpita/ Lari-

France.

for correspondance and reprints: Dr S. Balsan, HBpital des Enfants Malades. Laboratoire des Tissus CalcifiBs, Tour Technique 6’ Stage, 149, rue de SEtvres, 75730 Paris CBdex 15.

Address

Abstract The effectiveness of la-(OH)D3 treatment on the hyperparathyroidism that occurs in children on chronic hemodialysis was investigated. In the six children studied the vitamin D analog produced marked and rapid suppression of plasma iPTH concentrations. The therapy was well tolerated and no serious side effects of the treatment were observed. D3 - Hyperparathy Key Words: la-Hydroxyvitamin roidism - Children - Hemodialysis.

most patients maintained on chronic tiemodialysis circulating concentrations of immunoreactive parathyroid hormone (i.PTH) reach ten to twenty times the normal values (unpublished data). The present study was undertaken in six children on maintenance hemodialysis to investigate whether therapy with small doses of la-(OH)D3 could normalize or significantly decrease their plasma i.PTH concentrations, and to analyze the tolerance of these patients to long-term la-(OH)D3 therapy.

Subjects Introduction The therapeutic effectiveness of 1~hydroxyvitamin D3 (la-[OH)Dz), a synthetic vitamin D3 metabolite with biological potency similar to the renal metabolite i,25-dihydroxyvitamin D3 (I ,25-(OH)zD3), has been established by an increasing number of clinical trials. ln patients with renal osteodystrophy the beneficial effects of this drug on bone lesions have been shown by several investigators (Castells et al., 1976; Davie et al., 1976; Nielsen et al., 1976; Tougaard et al., 1976; Chan et al., 1977; Ellis et al., 1977; Junor and Catto, 1977; Kanis et al., 1977; Melsen et al., 1977; Naik et al., 1977; Peacock et al., 1977; Postlethwaite and Houston, 1977; Winney et al., 1977). Children, more than adults, are prone to develop skeletal lesions when afflicted with chronic renal disease (Balsan et al., 1966; Fine et al., 1972). However, as reported earlier (Witmer et al., 1976), in our department the percentage of children and adolescents with renal osteodystrophy has markedly decreased during the last decade. At the present time this complication is rare. It is observed in cases of late diagnosis or where preventive therapy has been lacking. Most of our patients reach the stage of terminal renal failure and maintenance therapy with normal radiograms on standard X-ray examination. However, when bone biopsies are performed on these patients, the lesions of hyperparathyroidism are evident (Witmer et al., 1976). Moreover, in

and Methods

Patients

Six patients, aged 6 to 15 years, were the subjects of this study. These patients were selected for this study because they were expected to remain under our care for at least one year. Table 1 summarizes their main clinical and biological data. These patients had been on maintenanse hemodialysis for periods varying from 4 months to 6 years. Three had had bilateral nephrectomy (patients 2, 3, and 61 2 years, 6 years, and 2 years respectively before the beginning of this investigation. In one child (patient 5) three hyperplastic parathyroid glands had been surgically removed at age four. All six children were on vitamin Dz or 25-(OHID therapy when the present investigation was initiated. These treatments were stopped for 12 days to one month before la-(OHID therapy. Daily intake of calcium (diet

starting

and oral supplementation of calcium) varied from 1 to 2 g/d and was maintained as such throughout the study. Additional medication, exchan e resins and/or phosphorus chelating drugs (aluminium R ydroxide gel) were prescribed and adjusted to the needs of the patients. Children were given a low protein diet [I to 2 g/Kg of body weight]. They received one polyvitamin capsule per day providing all water soluble vitamins and 12 &g/d (500 i.u./d) of vitamin 03. Three patients were on phenobarbital therapy. Maintenance

hemodialysls

Hemodialysis was performed with a disposable multilayer RP5 dialyser. Patients were dialyzed for eight hours two times

weekly.

The dialysate

was

prepared

with

softened

16

Sonia Balsan et al.: lz-Hydroxyvitamin

D3, Hyperparathyroidism,

Children,

Hemodialysis

water and a calcium concentration of 7.0 mg/lOO ml (3.5 mEq/l) and a magnesium concentration of 1.8 mg/ 100 ml (1.5 mEq/l).

6 pg/wk in some; treatment was transiently interrupted, respectively for one month and four months, in two cases (patients 3 and 5). Three

I z-hydroxyvitamin

patients were on chronic phenobarbital therapy and for one of these the dose of this drug had to be increased because of repeated seizures (patient 6).

03

The synthetic la-(OH)D3 was provided by Leo Pharmaceutical; Balrup, Denmark. It was given to the patients twiee immediately before dialysis. Treatment was weekly, started for all patients at the same period of the year (July-August 1975). The initial dose of la-(OHID was 4 pg/wk. This dose was increased to 6 pg/wk in case of persistent hypocalcemia (patient 5). hypophosphatemia (patient 6) or skeletal lesions on X-ray (patient 2). t,25-dihydroxyvitamain

D3

After 9 months of Id-lOHID one oatient was shifted to 1,25-(OH)ZD~ therapy. .The synthetii 1.25-(OH)zD3 given to this child was provided by Dr. M. Uskokovic, HoffmannLa Roche Research Laboratories, Nutley, New Jersey. This drug was used at doses varying from 3.5 to 10.5 pg/week. Radiological

evaluation

Standard radiograms were obtained a few days before initiating la-(OHID therapy, then every two to three months during the study. The radiograms were analyzed under a magnifying glass by three different investigators. When lesions were present, their severity was designated from + to + $ + according to criteria previously described (Witmer et al., 1976). For metaphyseal lesions the term sricketsm was used only for the abnormalities showing all the characteristics usually associated with nutritional rickets, i.e. widened metaphyseal-epiphyseal distances, cupped and enlarged metaphyses. Plasma chemistry Plasma calcium, phosphorus, total protein, and bicarbonate concentrations and plasma alkaline phosphatase activity were measured regularly: 4 to 8 times per month for plasma calcium and bicarbonate, 4 times per month for plasma phosphorus and total protein, and once a month for alkaline phosphatase. Circulating concentrations of 25(OHID and of iPTH were measured while the patients were still on their previous vitamin D3 or 25-(OHID therapy, then, at the beginning of la-(OHIDs, once monthly during the first six months. and on the twelfth month of treatment, then one to ten times during the second year of the study. Blood samples were obtained before dialysis. The following techniques were used: plasma calcium, atomic spectrophotometry (Perkin Elmer); plasma phosphorus, bicarbonate and total protein with an autoanalyser (Technicon, Domont, France); plasma alkaline phosphatase, Bodansky method during the first 14 morith!! of study: subsequently with a method adapted to an autoanalyser: plasma 25-(OH)D, a competitive protein-binding assay according to Preece et al. (1974). iPTH was measured using a C-terminal antibody (Arnaud et al., 1971). The results are expressed as ng protein of a standard hyperparathyroid serum, per ml of the patients serum.

Results The six patients studied do not form a homogeneous group, Three had undergone bilateral nephrectomy whereas the others, although in terminal stage renal failure, still had some glomerular function (Table II; one of the latter was bilaterally nephrectomized 4 months after the initiation of la-[OHIDs treatment. One child had one parathyroid gland after a 3/4 parathyroidectomy performed 4 years prior to the Also the dose of la-(OHIDs present investigatlon. used during the study was not constant in all patients. The doses were increased from 4 pglwk to

Only one child had severe X-ray lesions of osteitis fibrosa (patient I), whereas the others had minimal alterations or normal bone radiograms. Finally, three patients received a kidney transplant during the study (patients 4, 5, 6). For these reasons the biochemical parameters are presented on individual figures for each subject (Fig. 1 to 6). During the entire study none of the patients became acidotic and their total protein was normal. Plasma

iPTH concentrations

While still on their previous 25-(OH)D3 or vitamin Dz therapy all subjects had high concentrations of iPTH. The values varied from 55 to 200 ng/ml (normal values 4 to 8 ng/ml). These values are in the same range’ as the iPTH values observed in 21 patients from our center who were also on chronic hemodialysis and on 25-(OH)D3 therapy for at least one year. The highest concentrations were not necessarily found in bilaterally nephrectomized patients. Of interest is ,the observation that the child with one parathyroid gland had plasma iPTH concentrations similar to those of parathyroid intact subjects. Twelve days to one month after vitamin Dz or 25-(OH)D3 therapy was stopped the iPTH values During 1a-(OHID remained in the same range. therapy a marked fall in iPTH was observed in all A progressive decrease in iPTH, six patients. starting from the first month of treatment was obtained in two children (Fig. 3 and 5). For the others, 4 to 6 months of therapy were necessary. At this time, the iPTH concentrations of the six children were between IO and 32 ng/ml. An increase in iPTH was observed during the subsequent months of therapy in all the patients except in the parathyroidectomized child whose iPTH remained in the lo-32 ng/ml range and was normalized after 16 months of therapy (Fig. 3). However, for all these patients, except one (Fig. 6) the concentrations of iPTH remained between 30 and 50 ng/ml i.e. much lower than their basal values. In the last child (Fig. 6) plasma iPTH increased progressively after 4 months to concentrations similar to the prela-(OHID treatment values. For this patient la-(OHID therapy was replaced by 1,25-(OH)aD3 administered orally at doses varying from 3.5 pg to 10.5 pg/wk. On 1,25-(OH)zD3 her iPTH concentrations decreased again to 38 and 50 ng/ml. Plasma

calcium

concentrations

As shown on Fig. 1 to 6, the plasma calcium concentrations of most of these patients were low or in the low normal range when the study was initiated. Treatment with la-(0H)Ds resulted in an increase in plasma calcium in all but one patient (Fig. 61. This increase was particularly evident especially during the first four to eight months of therapy. An episode of hypercalcemia (plasma calcium concentrations 11.3 to 11.7 mg/l) occurred in two children after four and sixteen months of la-(OHIDs treatment respectively [Fig. 5 and 31. In both instances plasma calcium concentrations returned to normal values ten days to one month after cessation of la-(0H)Ds administration.

Sonia

Balsan

et al.:

Table I. Clinical

lx-Hydroxyvitamin

data

in six

patients

D3, Hyperparathyroidism,

on maintenance

Children,

hemodialysis,

17

Hemodialysis

before

lx-hydroxyvitamin

Vitamin

N0

yr

Height

mo

166

D

i

z

Weight

cm (SD)

Kg

102.3 [-3)

15.2

M

31

Sex

Cortical necrosis

OF tff

Dz

F

Neurologic bladder

OF +’

150

48

0.56

+

-

25-(0H)Ds

75

5

0.56

-

-

-

2

15

-

3

7

9

104.5 (-4)

16.5

F

Hemolytic uremic syndrome

Normal

25-(0H)Dz

100

18

1.2

+

3

4

IO

3

132.0 (--I)

25

M

Anaphylactoid purpura

Normal

25-[OH)D3

25

6

0.56

+

3

100.0 (-61

14.5

F

Cystinosis

OF +

25s(OHID

75

61.6

--

127.5 (-4)

24.5

F

Bartter syndrome

Normal

25-(OH)Ds

50

6

-

5 6

89 12

4

-

(a) yr = year (s); mo = month(,) OF nephrectomy; PTX = parathyroidectomy.

Plasma

phosphorus

(a).

Treatment

Patient Age

D3 therapy

=

osteitis

fibrosa;

Al

gel .=

aluminium

0.56

hydroxide

Bil NX + PTX3/4 Bil NX

5

gel:

Bil

NX

=

bilateral

concentrations

Due to the importance of individual variations in plasma phophorus and the fact that aluminum hydroxide gel therapy was prescribed according to the needs of each patient all effects of la-(OHID However, a general trend are difficult to analyze. towards a progressive rise in plasma phosphorus was observed in all six patients. This effect was particularly striking after 8 to 9 months of treatment.

iPTH

1nipa

A ~RqdO!llRll

Plasma

alkaline

phosphatase

Plasma alkaline phosphatase was normal in one child (Fig. 41, and slightly elevated in the others when la-(OHID therapy was begun. Except for patient number 6, alkaline phosphatase remained normal or decreased to normal values after three to four months of la-(OHID treatment. Plasma

25-(OHID

Pi

concentrations

High values of plasma 25-(OHID concentrations were found in the patients during their previous vitamin D When administrations of or 25-(0H)Ds therapy. 25-(OHID or vitamin D were stopped, plasma concentrations of 25-(OH)D3 decreased to normal levels. A subsequent rise in 25-(0H)D concentrations was observed in some patients (patients 2, 3, 4, 5). This may be related to an exceptionally sunny spring and summer in the year 1976.

Alk Pme

Nbd,ul

:;

Radiology

-3

Fig. 1: Variations

The severe lesions of osteitis fibrosa in one patient (patient 1J and the minimal alterations in two others (patients 2 and 5) disappeared after 4 to 6 months of therapy. During lac-(OHID treatment lesions of osteitis fibrosa appeared in one child, after her dose of phenobarbital was increased from 5 to 7.5 cg/d [patient 61. Three months later, while she was taking IO cg/d of phenobarbital, skeletal alterations wor-

1

3

6

9

12 15 M months

in plasma IPTH, calcium (Cal. phbsphorus (Pi), alkaline phosphatase [Alk-Pase], and 25-(OHID in patient 1. For all parameters except plasma phophorus the hatched area represents the normal range: for plasma phophorus it indicates the limit of acceptable hyperphosphatemia (6 mg/lOO ml]. Points with vertical bars represent the mean values t 1 SEM. Single points correspond to one measurement. Values obtained during previous vitamin Dz therapy are shown by crosses. Bod u = Bodansky units.

18

Sonia Balsan et al.: la-Hydroxyvitamin

D3, Hyperparathyroidism, Children, Hemodialysis

sened and her radiograms showed multiplie cortical resorption!% and the metaphyseal lesions of rickets. Treatment with increasing doses of 1,25-(OH)zD3 promoted the disappearance of the lesions of hyperparathyroidism and rickets. Evolution

in kidney

transplanted

subjects

Three children (patients 4, 5, 6) received a kidney transplant during the course of the study. The posttransplant period was uneventful in one (patient 5). Her plasma iPTH concentration decreased to near normal values (14 ng/ml) two months after transplant and remained so during the following four months of follow-up. In the other two patients (4 and 6) an increase in plasma iPTH was observed during the first month after kidney transplant. During this period the donor kidney did not function satisfactorily, necessitating repeated hemodialysis. However, in one of these children (patient 4) the plasma iPTH fell progressively, remaining at near normal concentration (18 to 14 ng/ml) from month 5 to month 13 after kidney transplant. In contrast, in the third patient (patient 6) despite 3.5 pg/d of 1,25-(OHlzD3 and plasma calcium concentrations that were in the normal range, her iPTH increased and remained very high (100 ng/ml). In this child donor kidney function never exceeded a glomerular filtration rate of 40 ml/ min/ 1.73 m2. One year after transplantation it was about 20 ml/min/l.73 m2. Steroid therapy could not be decreased to less than 2 mg/Kg/d for the first six months after kidney transplant without precipltation of a rejection crisis and this patient is still on high dose phenobarbital therapy (10 cg/d).

ca lm~~AOOrnl) i: 10 9 8 1

(mq~l00mll

i 7 6 5 4 3 2

lcr-(OHlD3

-3 1

Fig. 3: Variations

3

6

in plasma

9

12 15 I6 21 2C mmths

chemistry

arrow indicates the episode of transient observed for

figure

in this 1.

patient.

Other

symbols

in patient 3. The hypercalcemia are the same as

Discussion The radioimmunoassay of plasma iPTH used in the present investigation was carried out with a COOHterminal specific antiserum (Arnaud et al., 1971) and consequently detects intact PTH and its COOH-terminal fragments. Due to the slow clearance of these fragments COOH-terminal assays are not suitable for detecting acute secretory changes in the parathyroid However, these methods are useful for glands. assessing chronic hyperparathyroidism (Arnaud et al., 1974). The results obtained in the present investigation indicated that all patients were hyperparathyroid despite their previous vitamin Dz or 25(OH)D3 treatments. Five patients responded to long-term administration of small doses of la-(OHID with a marked decrease in their plasma iPTH concentrations. Such a decrease may be explained in two ways: 1) a diminution of PTH secretion, or 2) an increase in the disappareance rate of the intact hormone and its COOH-terminal fragments from plasma. There is no available data demonstrating that la-(OH)D3, or more precisely I ,25-(OH)zD3, the form into which IcG(OH)DJ is converted in the organism (Haussler et al., 1973 ; Holick et al., 1977) may increase the degradation of PTH. Hence, it may be reasonably assumed that the fall in plasma iPTH observed in these patients during Ia-(0H)Ds therapy, was a consequence of a diminution in parathyroid gland secretion. Flg. 2: Variations in plasma chemistry are the same as for figure 1.

in patient

2. Symbols

The change in the activity of parathyroid glands was not accompanied by a marked rise in total plasma

Sonia Balsan et al.: la-Hydroxyvitamin

D3, Hyperparathyroidism,

Plasma calcium increased calcium concentration. Moreover, slightly in most, but not all patients. except for two transient episodes of hypercalcemia, it remained in the normal range throughout the study. However, since ionized calcium concentrations were not measured, we cannot exclude the possibility that la-(OH)D3 action may have been mediated by a rise in circulating ionized calcium concentrations. It is also possible that the 1,25-(OH)zD3, derived from Ia-(OH)Ds, may have acted directly on the parathyroid glands, independent of any modifications in extracellular ionized calcium concentration (Cherow et al.. 1975; Capen et al., 1977). Of importance is the observation that plasma iPTH increased slightly during the last part of the study. This escape phenomenon from the suppressive effect of la-(OHID on parathyroid gland hyperactivity occurred in one patient during a progressive increase in her dose of phenobarbital (patient 6). This observation has been reported previously (Chan et al., 1977; Pierides et al., 19761. In the other children the escape seemed related to difficulties encountered in maintaining plasma phosphorus concentrations below 6.0 mg/ 100 ml. The rise in plasma phosphate observed in the patients, despite close medical surveillance can in all likelihood be explained by the well known effect of 1,25-(OH)zD3 and of its analog IOI-(OH)DB on intestine and bone (DeLuca, 1977) and the frequent lack Of compliance of most patients in taking their phosphate binders regularly.

Children,

19

Hemodialysis

la-Ion)03

The effects of la-(OHID or 1,25-(OH)zD3 on the bone lesions in chronic renal failure are well documented.

Fig. 5: Variations in plasma chemistry in patient 5. Symbols are the same as for figures 1 and 3. NX = bilateral nephrectomy: KT = kidney transplantation.

LL (np/lrnnl I

The therapeutic effectiveness of both drugs is high in children and adolescents (Castells et al., 1976; Nielsen, et al., 1976; Chan et al., 1977; Kanis et al., 1977; Postletwaite and Houston, 1977). Our present data are in agreement with reports from other investigators who show that small doses of la-(OHIDs or 1,25-(OH)2D3 can cure lesions of rickets and osteitis fibrosa in young’ patients witkrenai osteodystrophy. in contrast, failure of action of these two vitamin D derivatives have been reported in adult patients, especially in those with histological lesions of osteomalacia (Tougaard et al., 1976; Ellis et al.. 1977; Kanis et al., 1977). Some investigators have suggested that metabolites other than 1,25-(OH)2D3 may be necessary for a normal mineralization of bone tissue (Eastwood et al., 1977; Seber et al., 1977). In the phenobarbital treated child who developed severe lesions of rickets and of osteitis fibrosa, one year of 1,25-(OH)aD3 therapy promoted a complete healing of both types of lesions, although her plasma 25-(OHID had fallen to 4 ng/ml. Hence, in this particular patient it does not appear that a normal circulating concentration of 25-(OH)D3 is a prerequisite for 1,25-(OH)zD3 to promote healing of bone lesions.

”

10 9 I9

Alk

Rse

-3

'1

3

6

9

12

15

18

21

24

months

Fig. 4: Variations in plasma chemistry in:patkrpt 4.. Symbols are the same as for figure 1, KT = k&rtey transpkntation. Open circles indicate the values &SW.& afk~ -Iantation.

Despite %se of preventive therapy with vitamin ‘Dr or 25.(OH)D3 most children on long-term maintenance hemodiaiysis are hyperparathyroid even in the absence of radiologically detectable bone lesions. Since these patients are candidates for renal transplantation, it seems advisable to suppress their hyperparethyroidism as much as possible. Furthermore,

Sonia

20

Batsan

et al.:

isr-Hydroxyvitamin

03, Hyperparathyroidism,

serum in Arnaud, CD., of human 50: 21-34,

Children,

Hemodialysis

man. Am. J. Med. 56: 785-793, 1974. Tsao, H.S., Littledike. T.: Radioimmunoassay parathyroid hormone in serum. J. C/in. Invest. 1971.

Baisan, S., Royer, P.. Mathieu, H.: Les rachistimes et ies fibroosteociasies des insuffisances renaies chroniques de i’enfant. Arch. Fr. PBdiat. 23: 769-794, 1966. Capen, C.C., Henry, H.L., Norman, A.W.: Ultrastructural alterations produced by vitamin D and its metabolites on the chick parathyroid gland. in Vitamin D, Chemical and Clinical Aspects Related to Calcium Metabolism. Edited by A.W. Norman et al. (Edit) Walter de Gruyter, Berlin, New York, vol. 1: 101-104, 1977.

co m9dlOml)

,, 10

Casteiis, S., Shai, F., Gauthier, B., Hashemi, S.E., Reddi. C.H.. DeLuca, H.F.: Metabolic effects of Ir-hydroxy cholecalciferoi on renal osteodystrophy. Current Therap. Res. 19: 410-419, 1976.

9 6

p; lmqNIOml)

Chan, J.E.M., Oidham, S.B., DeLuca, H.F.: Effectiveness of la-hydroxyvitamin D3 in children with renal osteodystrophy associated with hemodiaiysis. J. Pediat. 90: 820-824, 1977.

l 7 b 5 b 3

Chatterjee, S., Firedier, R.M., Berne. T.V., Oldham, S.B.. Singer, F.R., Massry, S.G.: Persistant hypercaicemia after successful renal transplantation. Nephron 17: 1-7, 1976.

2

Cherow, B.S., Bayiink, K.J., Wergedal, J.E., Su, M.H.H., Norman, A.W.: Decrease in serum immunoreactive parathyroid hormone in rats in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol. J. C/in. Invest. 56: 668-678, 1975. Davie, M.M.J., Chamlers. T.M., Hunter, J.O., Peic. B.. Kodicek, E.: I-Aiphahydroxycholecalciferol in chronic renal failure. Studies of the effect of oral doses. Ann. Intern. Med. 64: 281-285, 1976. b_ 9

12 15

21 2C months

b. HI Fig. 6: Variations in plasma chemrstry In patient the top of the figure the closed horizontal bar represents doses of la-(OHID therapy, open horizontal bars dose 1,25-(OH]zD3. Symbols are the same as in figure 1 and 4. Notice the increasing dose of phenobarbital shown in the

lower part of the figure. experimental and clinical data indicate that aside from skeletal lesions hyperparathyroidism may have These changes may a number of consequences. occur even in subjects with normal total plasma calcium concentrations. Changes in the electroence. phalogram, possibly related to modifications in brain content of calcium (Arieff and Massry, 1974; Guisado et al., 1975); aggravated growth failure in children (Chan et al., 1977; Stickler and Bergen, 1973) arterial and muscular lesions in adults (Richardson et al., 1969), and a higher risk for aseptic necrosis of the femoral head (Chatterjee et al., 1976) are among the complications that occur more frequently in renal patients with hyperparathyroidism. The therapeutic effectiveness of small doses of la-(OH)D3, and ,the good tolerance of our patients to long-term therapy under strict and repeated biochemical controls, suggest that this analog of 1,25-(OH)zlL and 1,25-(OHlzD3 itself may be useful drugs for the prevention of skeletal and other alterations related to hyperparathyroidism in patients with chronic kidney diseases. References Arieff. A., Massry, in acute renal 1974.

S.G.: Calcium metabolism of brain failure. J. C/in. Invest. 53: 367392,

Arnaud, CD., Goldsmith, R.S.. Bordier, P., Sizmore, G.W.: Influence of immuno-heterogeneity of circulating parathyroid hormone on results of radioimmunoassay of

DeLuca, the 67:

H.F.: Recent advances in our understandina of vitamin D endocrine system. J. Lab. C/in. tied. 7-26, 1977.

Eastwood,

J.B., Stamp, T.C.B., de Wardener, H.E., Bordier, CD.: The effect of 25-hydroxyvitamln D3 in the osteomalacia of chronic renal failure. C/in. Sci. 52: 499-508, 1977.

P.J., Amaud,

Ellis,

H.A., Pierides, A.M., Feest, T.G., Ward, M.K., Kerr, D.N.S.: Histopathology of renal osteodystrophy with particular reference to the effects of la-hydroxyD3 in patients treated by long-term haemovitamin dialysis. C/in. Endocrinol. 7: suppl. 31%38s. 1977.

Fine, R.N., isaacson, A.S., Payne, V., Grushkin, CM.: Renal osteodystrophy in children: The effect of hemodialysis and renal homotransplantation. J. Pediat. 60: 243-249, 1972. Guisado, R., Arieff. A., Massry, S.G.: Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes. J. C/in. invest. 55: 738-745, 1975. Haussler, M.R., Zerwehk, J.E., Hesse, R.H.. Rizzardo, E.. Pechet, M.M.: Biological activity of icc-hydroxycholecaiciferol, a synthetic analog of the hormonal form of vitamin D3. Proc. Nat. Acad. Sci. 70: 22482252, 1973. Holick, M.F., deBlanco, MC., Clark, M.B., Henley, J.W., Neer. R.M., DeLuca, H.F.. Potts, J.T., Jr.: The metabolism of [6ZH] lc+hydroxycholecaiciferol to [6-3H] la-25-dihydroxychoiecaiciferoi in a patient with renal insufficiency. J. C/in. Endocrinol. 44: 595-598, 1977. Junor, B.J.R.. Catto, G.R.D.: The effect of la-hydroxyvitamin D3 on calcium and mineral content of bone in renal osteodystrophy. C/in. Endocrinol. 7: suppl. 131s-138% 1977. Kanis, J.A., Henderson, R.G., Heunen. G., J.G.G., Russei. R.G.G., Smith, R., Walton, osteodystrophy in one diaiysed adolescent. treatment with la-hydroxycholecaiciferol. Child. 52: 473-481, 1977.

Ledingham, R.J.: Renal Long-term Arch. Dis.

Sonia

Balsan

et

al.:

lz-Hydroxyvitamin

D3, Hyperparathyroidism.

Melsen, F., Nielsen. H.E., Christensen, MS.: Bone histomorphometry in patients with chronic renal failure: Effect of I%-hydroxyvitamin 03. C/in. Endocrine/. 7: suppl., 39s44s. 1977. Naik,

Children,

Hemodialysis

21

Richardson, J.A.. Herron, G., Reitz, R., Layzer, R.: lschemic ulcerations of skin and necrosis of muscle in azotemic hyperparathyroidism. Ann. Int. Med. 71: 129-138, 1969. Seber. J.L., Fournier, A., Gueris, J., Marie, P., Coevoet, B., defremont, J.F., Lambrey, G., Kuntz, D.: Osteodystrophie r&ale. I. Acquisitions physiopathologiques recentes. Nouvelle Presse Med. 6: 3419-3424, 1977.

R.B.. Dabek, J.T., Heynen, G., James,’ H.M.. Kanis. J.A., Robertson, P.W., Robinson, B.H.B., Woods, C.G.: Measurements of whole body calcium in chronic renal failure: Effects of iaThydroxyvitamin D3 and parathyroidectomv. C/in. EndocrinoI. 7: suppl.. 139s 145s 1977. .

Stickler, G.B., Bergen, B.J.: A review: Short sta ure in renal disease. Pediat. Res. 7: 978-982, 1973. \

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Received: March 15, 1978. Revised: April 25, 1978. Accepted: May 3, 1978.