- Email: [email protected]
Parathyroid function in uremic children during periods of renal insufficiency, hemodialysis, and transplantation
November 1976 The Journal o f P E D I A T R I C S
755
Parathyroid function in uremic children during periods of renal insufficiency, hemodialysis, and transplantation Function of the parathyroid gland was evaluated in children with renal insufficiency prior to and after initiation of hemodialysis, and again following renal transplantation. Serum levels" o f immunoreuctive parathyroid hormone responded appropriately to increases or decreases of serum calcium concentrations in the three groups. Functional and histologic studies in the children with renal insufficiency demonstrated the cause of their elevated circulating levels of iPTH to be diffuse parathyroid hyperplasia. During hemodialysis, the serum concentration of calcium rose and that of iPTH decreased, when the calcium gradient between the dialysate and the blood favored movement of calcium into the body. During treatment with prednisolone (20 mg/kg intravenously) for reversal of renal transplant rejection, the serum concentration of calcium decreased and that of iPTH increased. These observations suggest that autonomy of the parathyroid gland rarely occurs in children with renal insufficiency, and that hemodialysis using a diatysate with a high concentration of' calcium might assist in retarding the progression of renal osteodystrophy. Furthermore, if hyperparathyroidism contributes in part to growth failure in children with chronic renal disease, steroid-induced changes in eirulating iPTH Jbllowing renal transplantation may inhibit growth.
Alan B. Gruskin,* Allen W. Root, Gregory E. Duckett, and H. Jorge Baluarte, P h i l a d e l p h i a , Pa., a n d St. P e t e r s b u r g , Fla.
ALTERA1"IONS of the function of parathyroid gland occur during chronic renal insufficiency. Hypersecretion of parathyroid hormone contributes to the development and progression of renal osteodystrophy and to the growth failure of children with renal disease." '-'The cause of the hyperparathyroidism has been attributed to nonautonomously and autonomously functioning parathyroid From the Department of Pediatrics, Temple University School of Medicine, Section of Nephrology, St. Christopher's Hospital for Children and Department of Pediatrics, University of South Florida College of Medicine, and the Ed Wright Pediatric Endocrinology Research Laboratory, All Children's Hospital. Supported in part from the National Institutes of Health General Clinical Research Center (RR-75), General Research Support (RR-5624) and Research Grants HD-04840, HD-08313, IRO1-HE-12651-02, and National Foundation. *Reprint address: St. Christopher; Ho.~pitalfor Children. 2600 N. Lawrence St., Philadelphia, Pa. 19133.
glands? Control of the hyperparathyroidism has been accomplished by performing dialysis with a high concentration of calcium in the dialysate.* Following renal transplantation in children, the rate Of growth as well as the serum concentration of calcium are inversely related to the quantity of corticosteroids administered? Abbreviations used iPTH: immunoreactive parathyroid hormone Cat: total serum calcium P~: inorganic phosphate This study was based on the above observations and designed to explore the following questions: (1)Are the parathyroid glands in children with renal insufficiency functioning autonomously? (2) If parathyroid autonomy does not exist, might hemodialysis against high levels of calcium in the dialysate solution be helpful in avoiding the progression of renal osteodystrophy? (3) Might delay
Vol. 89, No. 5, pp. 755-762
756
Gruskin et al.
The Journal of Pediatrics November 1976
Table I. Clinical data, renal function, baseline serum values and radiographic diagnoses in children with chronic renal disease Renal function
Baseline serum values
Clearance ml/ rain 1.73m ~ Patient
Age
M.K.
10 4/12 11 8/12 12 9/12 3 6/12
G.I. F.R. A.H.
Calcium infusion
Glucagon injection
Radiographic diagnoses
Calcium Phosphates iPTH Calcium Phosphates iPTH Osteomalacia HyDerDaraDiagnosis [GFR PAH Urate TRP (mg/dl) (mg/dl) (pg/ml) (mg/dl) (mg/dl) (Dg/ml) or rickets thyroidism OU
28 ~
157
17
54
8.4
4.2
1,327
9.5
4.2
1,143
0
Mild
ATD
17~
85
7
27
7.9
6.0
1,515
7.6
5.8
1,534
Mild
Mild
CPN
841
303
12
77
9.4
5.1
133
8.9
5.0
201
0
0
HK
8~
-
14
36
10
2.5
342
9.5
7.1
2,404
Severe
Severe (parathyroidectomy) Severe (parathyroidectorny) Severe
J.B.
9 3/12
C
13"
-
45
39
8.5
3.8
375
7.9
Not done
430
Severe
T.C,
4 1/12
OU
38 ~
100
11
41
8.3
4.2
1,655
9.7
5.1
1,630
Severe
GFR = glomerular fiti'ation rate; PAH = para-aminohypurate; TRP = tubular reabsorption of phosphate; iPTH = immunoreactiveparathyroid hormone; OU = obstructive uropathy; ATP = asphyxiating thoracic dystrophy; CPN = chronic pyelonephritis; HK = hypoplastic kidneys; C = cystnosis.
in resumption of growth following renal transplantation be related to hyperparathyroidism induced or perpetuated by corticosteroids?
MATERIALS AND METHODS Our studies were performed in three groups of children. Group I included six children who had renal insufficiency but had not required hemodialysis. Group II included four children who were receiving hemodialysis regularly. Group III consisted of five children who were treated for seven episodes of acute renal transplant rejection. Studies in the first group were designed to establish whether there was autonomous function of the parathyroid glands. Those studies in the second group were designed to determine whether a high concentration o f ionized calcium in the dialysate solution would suppress circulating levels of immunoreactive parathormone. The studies in Group III were designed to determine if acute changes in circulating levels of calcium and i P T H occur after the administration of large doses of corticosteroids. The type of study and the potential risks were explained to the family of each child, and informed consent was obtained. The three study protocols were approved by the H u m a n Research Committee of St. Christopher's Hospital for Children. Group I (chronic renal insufficiency). The clinical features of the renal disease in these children are summa-
rized in Table I. Their concentrations of total serum calcium were elevated or lowered and the concurrent changes in serum levels of iPTH and inorganic phosphate monitored. In four children (M. K., G. I., F. R., A. H.) an attempt was made to lower the serum concentration of C a t by administering glucagon in a dose of 1 mg intravenously or 2 mg intramuscularly. Serum specimens were obtained prior to and at 15-minute intervals for two to five hours following injection of glucagon. In these four children and also in Patients J. B. and T. C., the serum concentration of Cat was increased by infusing calcium salts intravenously. The infusions of calcium salts were performed on the day following the glucagon study except in Patient A. H. (16 days after receiving glucagon). Infusions of inulin and para-aminohippurate were performed, and timed collections of urine and serum specimens were obtained to quantitate renal function. Subsequently, the equivalent o f 4 m g / k g / h o u r of elemental calcium was infused in the form of calcium gluceptate for four hours. Blood samples were obtained prior to, during the calcium infusion, and for periods of two to four and one-half hours afterward. Group II (hemodialysis). In four children, the changes in the serum levels of Cat, P~, and iPTH were determined over a period of five hours of hemodialysis. Simultaneous blood samples were drawn from the arterial and venous lines attached to the dialysis coil. The concentration of
Volume 89 Number 5
Parathyroid function in uremic children
757
T a b l e It. Clinical data a n d changes in B U N a n d creatinine values before a n d after dialysis; o n e - h a l f o f a new T r a v e n o l coil, ultraflo, was used for each child
Creatinine BUN (mg/dl) Patient
No. of hemodialyses
Diagnosis*
Age
Coil
W.T.
93
CGN
16 3/12
49
C.H.
11
CGN
10 2/12
19
M.L.
69
CPN
9 11/12
22
W,W.
13
CGN
12
28
1/2 UF 100 1/2 UF 60 1/2 UF 100 1/2 UF 100
8
l] Degree of renal osteodystrophy
66
42
11.8
Moderate
76
26
9.6
4.4
Severe
56
20
8.6
3.7
Severe
99
37
7.7
3.6
None
BUN = Blood urea nitrogen; UF = ultraflo; CGN = chronic glornerulonephritis; CPN = chronic pyelonephritis. T a b l e III. Clinical data a n d baseline serum values in children with renal transplants
Patient M.L.
A ge
Diagnosis
W.W. J.B. M.I.
9 9 12 9 17
6/12 ' 10/12 1/12 7/12 11/12
CPN CGN FN ATD
R.C.
15
1/12
CGN
Days r transplantation
Serum calcium (mg/dl)
Inorganic phosphate (mg/dl)
iPTH (pg/ml)
BUN (mg/dl)
Transplant 1, 54 Transplant 2, 8 22 28 368 369 262
7.6 9.0 8.9 8.5 9.6 10.2 9.8
3.4 2.6 4.9 3.4 4.0 3.5 4.3
1,918 716 258 606 246 119 1,000
58 35 22 44 19 21 19
Crealinine (mg/dl) 3.0 2.0 0.9 1.2 1.4 1.3 2.0
CPN = Chronic pyelonephritis; CGN = chronic glomerulonephritis; FN = familial nephritis; ATD = asphyxiating thoracic dystrophy. ionized calcium in the dialysate at the b e g i n n i n g o f dialysis was 7 to 8 m g / d l . T a b l e I | contains the clinical diagnosis o f each child, type of dialysis coil used, a n d the changes in serum levels o f urea nitrogen a n d creatinine that occurred during dialysis. Group Ill (post-transplantation studies). T h e age, diagnosis, n u m b e r o f days after transplantation, a n d p r e t h e r a p y serum levels of Cat, Pi, a n d i P T H in the five patients treated for t r a n s p l a n t rejection are listed in Table III. After o b t a i n i n g two samples o f p r e t r e a t m e n t blood 30 m i n u t e s apart, seven episodes of t r a n s p l a n t rejection were treated with a o n e - h o u r i n t r a v e n o u s infusion containing 20 m g / k g o f prednisolone. After completing the infusion, changes in serum concentrations of Cat a n d i P T H were d e t e r m i n e d at intervals o f one to two h o u r s for periods o f six to 12 hours. Procedure. In all three groups, the s e r u m was separated i m m e d i a t e l y from the red blood cells a n d frozen until analyzed. S t a n d a r d m e t h o d s for m e a s u r e m e n t o f levels of total serum calcium, 6 phosphates, 7 urea nitrogen, ~ creatinine/~ uric acid, TM inulin, H a n d P A H ~'-'were employed. T h e
duplicate d e t e r m i n a t i o n s of solute and iPTH were p e r f o r m e d in separate laboratories, each being u n a w a r e o f the other's results. All o f the d e t e r m i n a t i o n s for iPTH in any single Patient were p e r f o r m e d simultaneously. Levels of i P T H were d e t e r m i n e d by a r a d i o i m m u n o a s s a y described in detail elsewhere? ~ Using this assay, the m e a n value for iPTH concentration in 76 n o r m a l children from one to 18 years of age was 125 - 70 SD p g / m l . 13 The coefficient of variation f o u n d in multiple d e t e r m i n a t i o n s using serum from a patient with h y p e r p a r a t h y r o i d i s m was 10.7%? ~ T h e assay recognizes the antigenic site n e a r the a m i n o terminus.
RESULTS Group !. Glucagon injection.
Preinjection values for serum concentrations o f Cat, Pi, a n d iPTH are presented in Table I. A significant decrease in serum levels of Ca, and P, occurred within a n d persisted for 60 m i n u t e s in three of the four children (Fig. i). In the fourth child, n o c h a n g e in the concentration of Ca~ was seen until 240 minutes after
758
Gruskin et al.
The Journal of Pediatrics November 1976
21
1.8-"--~
9 MK /
~~
.16-
~176
2
1.0--
...... ~"................ "
l.u --i
I
..., ........ 9...................
............ 1 . . * ....... . 0
< >
0.8--
>
E
1.2--
, . " - - F.
~
'
2
"MTcKG
~
+
1.4
t - - ~ . ~
1.2--
0
iJ
z 0
§
~-J
+
.].
I.I--
t .0--
"**" TC " MK
1.2--
/[--
~MK ,*MK
1 . 0 . _ . ~ _ _ ~ . ~ - - - - ~ - ~
~ ....
~AH
~
us
1,0--
<
o.9
:E
,B
>
.-i
>
AN
FR
/~
0.9--
t
b" 1.4-~ 1
/
/
,,v r
2:) ,v
0.8--
us
Te
1.6--r-
GI
1.4--
MK
1.21.0
FR
r";L....
0.8 (3
I
I
I
I
I
I
I
1 0.2
Iol
I ol ~1 ~l ,::,1 I I
MINUTES AFTER G L U C A G O N Fig. 1. Relative changes in the serum levels of total calcium. phosphorusj and iPTH following administration ofglucagon. The ordinate is a time axis. Values shown on the abscissa indicate changes from control values which were obtained by dividing control values by subsequently obtained values at the stated intervals. Serum concentrations corresponding to control values for individual children are provided in Table I. the injection of glucagon. The ranges of m a x i m u m decreases for serum concentrations of Ca~ and P~ were from 0.2 to 1.3 mg/dl and 0.3 to 1.0 mg/dl, respectively. There were no changes in levels of iPTH during the first 60 minutes; however, during the n e x t 60 minutes, the serum level of iPTH increased by more than 20% in the three children whose serum concentration of Cat had fallen. Calcium infusion. In five of the six children with renal insufficiency, elevated serum levels of iPTH and depressed inulin and PAH clearances to less than 25% of normal values were noted (Table I). The percent of tubular phosphate reabsorbed in these five patients was depressed, During each infusion of calcium, the serum concentrations of Ca~ increased, while serum levels of iPTH fell. Serum concentrations of iPTH decreased by
L ~'~
,v c A , c , u M 4mg/kg/hr
.I "7
MINUTES FROM ONSET OF CALCIUM INFUSION Fig. 2. Relative changes in serum values of calcium, phospl~orus, and iPTH following intravenous infusions of calcium gluceptate (4 mg/kg/hr for 4 hours). The plotting methodology is similar to that of Fig. 1. Serum concentrations corresponding to control values for individual children are provided in Table 1.
more than 60% in all patients (Fig. 2), and in three attained normal levels. However, serum levels of {PTH returned to preinfusion levels within two hours after discontinuation of intravenous calcium salts. Serum concentrations of P~ tended to rise during the calcium infusion. Group I 1 . W h e n dialyzed against a dialysate containing an ionized calcium concentration of 7 to 8 mg/dl, serum concentrations of Ca~ increased and levels o f i P T H and P~ decreased during hemodialysis (Table IV). Ca~ concentrations in the venous blood lines (coil to body) were always higher than in the arterial lines. Calcium, then, was always moving from dialysate to child. The similarity between
Volume 89 Number 5
Parathyroid function in uremic children
75 9
Table IV. Changes in arterial and venous values during hemodialysis
Hours ofhemoda@sm Laboratory examination
Patient W.T.
Serum calcium (mg/dl) Inorganic phosphate (mg/dl)
C.H.
iPTH (pg/ml) Serum calcium Phosphate
M.L.
iPTH Serum calcium Phosphate
W,W.
iPTH Serum calcium Phosphate
Source
1/4
1
3
Arterial Venous Arterial Venous Arterial Arterial Venous Arterial Venous Arterial Arterial Venous Arterial Venous
8.9 9.0 5.7 5.9 ~0 9.0 10.0 6.5 6.4 553 9.8 10.6 2.9 2.3 283 7.4 8.3 8.2 6.0 1079
9.0 11.3 5.5 4.0 285 9.8 10.6 5.7 4.6 503 11.0 11.6 2.7 2.1 233 8.1 9.1 7.6 5.3 969
9.4 11.4 5.3 4.8 253 10.0 11.0 5.2 4.3 448 11.1 12.0 2.7 1.9 230 8.7 9.6 6.9 4.6 536
Arterial Venous Arterial Venous
iPTH
the concentrations ofiPTH in the arterial and venous lines suggests that hemodialysis does not remove iPTH from the serum. Two children attained normal serum levels of iPTH. No correlation between the clinical or radiographic severity of renal osteodystrophy and serum levels of iPTH was found in the children in Group I and those in Group II. Patients A. H. and J. B. (Group I) had subtotal parathyroidectomies within one month following these studies. The level of circulating iPTH in Patient A. H. fell from 2,404 to 342 pg/ml during in-hospital therapy with Basaljel, a phosphate-binding aluminum salt. Although each child attained normal serum levels of iPTH during the calcium infusion, the lack of patient a n d family compliance with conservative medical management necessitated surgery. Each child had radiographic evidence of severe hyperparathyroid bone disease. The weights of the parathyroid tissue removed from Patients A. H. and J. B. were 8.0 and 4.5 times, respectively, that expected in the normal child. TM Histologic examination revealed diffuse parathyroid hyperplasia. Group IIl. The baseline information relative to this group is summarized in Table III. Serum concentrations of Cat decreased following six of the seven one-hour intravenous infusions containing 20 mg/kg of prednisolone intended to reverse renal transplant rejection (Fig. 3). The range of maximum depression of serum concentrations of Cat was 0.2 to 1.4 mg/dl. Specimens of serum for
I
i
5 9.8 13.0 5.0 3.6 240 10.2 11.6 5.0 3.9 390 12.4 12.8 2.4 1.8 193 9.1 10.1 6.4 4.0 328
determining Cat were unavailable from the seventh study. Serum concentrations of Cat remained depressed for six to 12 hours following the infusion of prednisolone in five of the six studies. Serum levels of iPTH increased by at least 50% in five of the seven studies. A consistent change in the serum level of P~ was not observed. DISCUSSION Suppression of serum levels of iPTH toward normal could regularly be achieved in our patients by elevation of the serum concentration of Cat, whether by infusion of calcium salts as in Group I or by hemodialysis against a dialysate with a high concentration of ionized calcium in Group II. This suggests that functional autonomy of the parathyroid gland did not exist in any of these uremic children. Calcium infusion resulted in increases of serum Cat concentration of at least 25% and reduction of levels of iPTH of more than 60% in all five of the uremic children in Group I, irrespective of the degree of severity of their renal osteodystrophy. Roof and coworkers, ~5 on the other hand, found that intravenous infusion of calcium salts suppressed serum levels of iPTH with certainty only in 14 uremic patients who did not have roentgenographic evidence of renal'osteodystrophy. In 17 patients with radiographically apparent bone disease, higher preinfusion levels of iPTH and smaller reductions of iPTH.concentrations during infusion of calcium salts were observed. In fact, levels of iPTH did not decrease in
760
Gruskin et al.
The 4~ournalof Pediatrics November 1976
1.05-~
"> :
"< 89
.........
.85 ~' O
~ U
.80
2.5
.J,
ILl ,=a
t
2.0--
/"~
...--'"~'""~~
ww
.,( > zE I,LI
1.0-- ,..'2".
-
"--M~
................................... Fie
.75
I 0
( 2
I
I 4
I
( I I 6 8
I
I I I i0 12
HOURS AFTER INTRAVENOUS PREDNISOLONE Fig. 3. Relative changes in serum values of calcium and iPTH following intravenous infusions of prednisolone (20 mg/kg). The plotting method is similar to that of Fig. 1. Serum concentrations corresponding to control values for individual children are provided in Table IlI.
five of their patients. A difference between Roof and associates' studies and the present one is that we infused a greater amount of calcium: 16 mg/kg/4 hours of elemental calcium equivalent compared to 10 mg/kg/3 hours (26 patients) 1~ or 15 mg/kg/4 hours (15 patients).l~ Lack of parathyroid autonomy in uremic children was not so evident when reduction of serum Cat concentration was used to stimulate PTH secretion. Glucagon, the agent used in Group I to lower serum concentrations of Cat, acts by increasing the uptake of calcium by bone and does not require the presence of either the thyroid gland or kidney to effect its change. 16 17Elevation of serum levels ofiPTH occurred in only three of the four patients studied after administration ofglucagon. The fourth patient, A. H., had diffuse parathyroid hyperplasia. These findings in addition to previous studies showing that serum concentrations of iPTH increase in patients with parathyroid adenoma following EDTA-induced reduction of serum Cat TM indicate that pharmacologic maneuvers which lower serum calcium may not differentiate autonomous from suppressible parathyroid function. Our observations have several therapeutic implicationsi In children with renal insufficiency who are not receiving hemodialysis, parathyroid gland function is not autonomous and therefore vigorous, persistent medical therapy should limit the degree of renal osteodystophy. However,
this .goal might be an unrealistic expectation in some children because of their failure to adhere to rigid medical and dietary regimens. Patients A. H. and J. B. required subtotal parathyroidectomy for Control of renal osteodystrophy in spite of our being able to suppress their serum iPTH to normal values by the intravenous infusion of calcium salts and/or adequate reduction of serum Pi concentrations with oral aluminun~ salts. Levels of iPTH were also able to be suppressed to normal values in the presence of a large mass of hyperplastic parathyroid tissue in these children. These observations are at variance with those of others who were unable to inhibit parathormone synthesis in animals in which the mass of parathyroid tissue had been artifically increased. 1~.... The studies in Group I I as well as others 2~demonstrated that when hemodialysis is performed using a dialysate concentration of ionized calcium greater than 7 mg/dl, transient decreases in levels of iPTH during dialysis and concurrent elevations of serum concentrations of Cat occur. Such observations suggest that hemodialysis against a high dialysate concentration of ionized calcium should be effective therapy for renal bone disease. .... Patients dialyzed with a high dialysate concentration of calcium may have normal sized parathyroid glands at autopsyr Some investigators, however, feel that the use of high concentrations of calcium in the dialysate does not retard progression of osteodystrophy2 ~' '-'~Since the use of a high concentration of calcium in the dialysate transiently suppresses parathyroid function, the reason for the differences between these opinions may be related to the type of therapy used to suppress parathyroid function between dialyses. In the children of Groups I and II there was no correlation of serum levels of iPTH with the extent of radiographically demonstrable renal osteodystrophy. Potter and co-workers '-'~have also shown that the degree of renal bone disease in children correlates with the duration of renal insufficiency rather than with the serum level of iPTH. Metabolic bone disease in children with renal insufficiency may cause severe skeletal deformities and may also be one of the more important factors contributins to growth retardation in these children. -~4Although autonomy of the parathyroid gland only rarely occurs as part of the spectrum of renal disease, medical therapy for secondary hyperparathyroidism may fail in all children to control the progression of their osteodystrophy, and parathyroidectomy may be necessary. Relatively few children have been reported to have had subtotal or total parathyroidectomy for renal osteodystrophy.-" '-'~In general, parathyroidectomy has resulted in healing of bone fractures, and the growth rate of these children has improved.'-'
Volume 89 Number 5
The acute response of serum Ca t and iPTH levels to corticosteroid administration has not previously been reported in patients receiving large doses o f prednisolone (20 mg/kg) for the treatment of transplant rejection. Following renal transplantation the doses of corticosteroids in relation to body weight for control of rejection are much greater than doses used for the therapy and differential diagnosis of hypercalcemia. ~ Our studies suggest that the administration of sufficient quantities of corticosteroids may influence both the serum levels of Ca t and iPTH. Popovtzer and associates 27 reported that, following renal transplantation, the levels of serum calcium are inversely related to the total dose of prednisone and that, w h e n the dose of prednisone is lowered, serum levels of Cat often increase. Corticosteroids may also increase levels of i P T H by 72% without changing levels of Ca~. ~8 The changes in Cat in patients following predniso!one infusions occurred too rapidly to be attributed to the known capacity o f corticosteroids to decrease calcium transport across the bowel. -~'~Changes in serum levels of Pi were not consistent and cannot explain the decreases in serum levels of Ca t in our patients. Corticosteroid administration also does not cause hypocalcemia by lowering serum protein concentrations? ~ Although hypocalcemia and increases of iPTH both occur in association with acute reduction of renal function, ~ our observations cannot be explained by loss of renal function associated with transplant rejection episodes. In some of the patients, further reduction of renal function did not occur, while in others anti-rejection therapy was instituted prior to measurable change in glomerular filtration rate. Steroid-induced decreases in serum Cat concentration also cannot be explained by an increased rate of excretion o f calcium, since calcium excretion decreases after the rapid intravenous administration of high doses of prednisoneY-' The mechanism for the reduction of serum C.a t may possibly reflect increases in circulating glucagon related to chronic steroid therapy. Oral prednisone at a dose of 40 to 60 m g / d a y for three days in normal adults increased fasting serum levels of glucagon, but the intravenous infusion of I00 mg of prednisolone over five minutes did not? 3 Finally, a reduction in the serum concentrations of Cat may be due to steroid interference with PTH-induced calcium release from bone? ~ These studies demonstrate a reduction in serum levels of Cat and elevation in i P T H following massive individual doses of intravenous corticosteroids. They suggest that the complex interplay of corticosteroids, glucagon, and parathormone may contribute to depression of growth in children receiving chronic corticosteroid therapy and to delay in resumption of growth following renal transplantation. The onset of growth following transplantation is
Parathyroid function in uremic children
76 1
related to the amount o f corticosteroid ingested during the post-transplant period? The authors express their appreciation to the nursing staffs of the Hemodialysis Unit and Clinical Research Center of St. Christopher's Hospital for Children for their help in performing these studies, to Deborah Troyanosky, renal technologist, to Drs. V. C. Vaughan III and L. Hiner for reviewing the manuscript, and to Sandra Turner for her secretarial assistance. REFERENCES
1. Fine RN, Isaacson AS, Payne V, and Grushkin CM: Renal osteodystrophy in children. The effect of hemodialysis and renal homotransplantation, J PEDIArR 80:243, 1972. 2. Firor HV, Moore ES, Levitsky LK, and Galvez M: Parathyroidectomy in children with chronic renal failure, J Pediatr Surg 7:565, 1972. 3. Popowniak KL, Esselstyn CB Jr, and Nakamoto S: Parathyroidectomy for the treatment of renal osteodystrophy and tertiary hyperparathyroidism: Progress report, Surg Clin North Am 54:325, 1974. 4. Fournier AE, Arnaud CD, Johnson W J, Taylor WF, and Goldsmith RS: Etiology of hyperparathyrgidism and bone disease during chronic hemodialysis, J Clin Invest 50:599, 1971. 5. Hoda Q, Hasinoff DJ, and Arbus GS: Growth following renal transplantation in children and adolescents, Clin Nephrol 3:6, 1975. 6. Conboy J, Davis M, and Gott JD: Statistics of a fluorometric calcium determination, Am J Clin Pathol 53:196, 1970. 7. Gomori G: A modification of the colorimetric phosphorus determination for use with the determination of blood urea, Clin Chem 11:624, 1965. 8. Marsh WH, Fingerhut B, and Miller H: Automated and manual direct methods for the determination of blood urea, Clin Chem 11:624, 1965. 9. Bonsnes RW, and Taussky HH: On the colorimetric determination of creatinine by the Jaffe reaction, J Biol Chem 158:581, 1945. 10. Caraway WT: Determination of uric acid in serum by a carbonate method, Am J Clin Pathol 25:840, 1955. 11. Walser M, Davidson DG, and Orloff J: The renal clearance of alkali-stable inulin, J Clin Invest 342:1520, 1955. 12. Smith HW, Finkelstein N, Aliminosa L, Crawford B, and Grader M: The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man, J Clin Invest 23:388, 1945. 13. Root A, Gruskin A, Reber RM, Stopa A, and Ducker t G: Serum concentrations of parathyroid hormone in infants, children and adolescents, J PEDIATR85:329, 1974. 14. Gilmour JR, and Martin WJ: The weight of the parathyroid glands, J Pathol Bact 44:431, 1937. 15. Roof BS, Piel CF, Rames L, Potter D, and Gordon GS: Parathyroid function in uremic children with and without osteodystrophy, Pediatrics 53:404, 1974. 16. Williams GA, Bowser EM, and Henderson WJ: Mode of hypocalcemic action of glucagon in the rat, Endocrinology 85:537, 1969. 17. ~fanzer FS, Kennedy JW, and Talmage RV: A comparison of the effects of thyrocalcitonin and glucagon on plasma
762
18.
19.
20.
21.
22.
23.
24. 25. 26. 27.
Gruskin et aL
calcium and phosphate, Proc Soc Exp Biol Med 133:500, 1970. Murray TM, Peacock M, Powell D, Monchik JM, and Ports JT Jr: Non-autonomy of hormone secretion in primary hyperparathyroidism, Clin Endocrinol 1:235, 1972. Gittes RF, and Rudde IC: Experimental hyperparathyroidism from multiple isologous parathyroid transplants. Homeostatic effect of simultaneous thyroid transplants, Endocrinology 78:1015, 1966. Gittes RF, and Radde IC: Experimental model of hyperparathyroidism: Effect of excessive numbers of transplanted isologons parathyroid glands, J Urol 95:595, 1966. Goldsmith RS, Forxzyfer J, Johnson W J, Fournier AE, and Arnaud CD: Control of secondary hyperparathyroidism during long term hemodialysis, Am J Med 50:692, 1971. Potter DK, Wilson C J, and Ozonoff MB: Hyperparathyroid bone disease in children undergoing longcterm hemodialysis treatment with vitamin D, J PEDIATR 85"60, 1974. Eastwood JB, Bordier J, and DeWardener HE: Some biochemical, histological, radiological and clinical features of renal osteodystrophy. Kidney lnt 4:128, 1973. Stickier GB, and Bergen BJ: A review: Short stature in renal disease, Pediatr Res 7:978, t973. Ogg CS: Parathyroidectomy in the treatment of secondary renal hyperparathyroidism, Kid lnt 4:168, 1973. Dent CE, and Watson L: The hydrocortisone test in primary and tertiary hyperparathyroidism, Lancet 2:662, 1968. Popovtzer MM, Geis WP, and Starzl TE: Hyperparathyroidism after kidney homotransptantation. 1. Relation to homograft function, in Hioco D, editor: International
The Journal of Pediatrics November 1976
28.
29.
30.
31.
32.
33.
34.
Symposium on kidney and calcium, Sandoz Editions, les trios epis, Paris, December 14-17, 1972, Ruel-Malmaison, p 145. Fucik RF, Kukreja SC, Haryis GD, Bauser EN, Henderson W J, and Williams GA: Effect of glucocorticoids on function of the parathyroid glands in man, J Clin Endocrinol Metab 40:152, 1975. Favns MJ, Kimberg DV, Miller GN, and Gershon E: Effects of cortisone administration in the metabolism and localization of 25-hydroxycholecalciferal in the rat, J Clin Invest 52:1328, 1973. Williams GA, Peterson WC, Bowser EN, Henderson W J, Hargis GK, and Martinez N J: Interrelationship of parathyroid and adrenocorticat function in calcium homeostasis in the rat, Endocrinology 95:707, 1974. Massry SG, Coburn JW, Lee DBN, Kleeman J J, and Kleeman CR: Skeletal resistance to parathyroid hormone in renal failure, Ann Intern Med 78:357, 1973. Popovtzer MM, Pinggera WG, Robinette J, Holmes JH, Holgrimson CG, and Starzl TE: Acute renal response to large dose of intravenous prednisolone in kidney homograft recipients and in normal subjects, J Lab Clin Med 78:39, t974. Wise JK, Hendler R, and Felig P: Influence of glucocorticoids in glucagon secretion and plasma amino acid concentrations in man, J Clin Invest 52:2774, 1973. Eliel LP, Thomsen C, and Chanes R: Antagonism between parathyroid extract and adrenal cortical steroids in man, J Clin Endocronol 25:457, 1965.
755
Parathyroid function in uremic children during periods of renal insufficiency, hemodialysis, and transplantation Function of the parathyroid gland was evaluated in children with renal insufficiency prior to and after initiation of hemodialysis, and again following renal transplantation. Serum levels" o f immunoreuctive parathyroid hormone responded appropriately to increases or decreases of serum calcium concentrations in the three groups. Functional and histologic studies in the children with renal insufficiency demonstrated the cause of their elevated circulating levels of iPTH to be diffuse parathyroid hyperplasia. During hemodialysis, the serum concentration of calcium rose and that of iPTH decreased, when the calcium gradient between the dialysate and the blood favored movement of calcium into the body. During treatment with prednisolone (20 mg/kg intravenously) for reversal of renal transplant rejection, the serum concentration of calcium decreased and that of iPTH increased. These observations suggest that autonomy of the parathyroid gland rarely occurs in children with renal insufficiency, and that hemodialysis using a diatysate with a high concentration of' calcium might assist in retarding the progression of renal osteodystrophy. Furthermore, if hyperparathyroidism contributes in part to growth failure in children with chronic renal disease, steroid-induced changes in eirulating iPTH Jbllowing renal transplantation may inhibit growth.
Alan B. Gruskin,* Allen W. Root, Gregory E. Duckett, and H. Jorge Baluarte, P h i l a d e l p h i a , Pa., a n d St. P e t e r s b u r g , Fla.
ALTERA1"IONS of the function of parathyroid gland occur during chronic renal insufficiency. Hypersecretion of parathyroid hormone contributes to the development and progression of renal osteodystrophy and to the growth failure of children with renal disease." '-'The cause of the hyperparathyroidism has been attributed to nonautonomously and autonomously functioning parathyroid From the Department of Pediatrics, Temple University School of Medicine, Section of Nephrology, St. Christopher's Hospital for Children and Department of Pediatrics, University of South Florida College of Medicine, and the Ed Wright Pediatric Endocrinology Research Laboratory, All Children's Hospital. Supported in part from the National Institutes of Health General Clinical Research Center (RR-75), General Research Support (RR-5624) and Research Grants HD-04840, HD-08313, IRO1-HE-12651-02, and National Foundation. *Reprint address: St. Christopher; Ho.~pitalfor Children. 2600 N. Lawrence St., Philadelphia, Pa. 19133.
glands? Control of the hyperparathyroidism has been accomplished by performing dialysis with a high concentration of calcium in the dialysate.* Following renal transplantation in children, the rate Of growth as well as the serum concentration of calcium are inversely related to the quantity of corticosteroids administered? Abbreviations used iPTH: immunoreactive parathyroid hormone Cat: total serum calcium P~: inorganic phosphate This study was based on the above observations and designed to explore the following questions: (1)Are the parathyroid glands in children with renal insufficiency functioning autonomously? (2) If parathyroid autonomy does not exist, might hemodialysis against high levels of calcium in the dialysate solution be helpful in avoiding the progression of renal osteodystrophy? (3) Might delay
Vol. 89, No. 5, pp. 755-762
756
Gruskin et al.
The Journal of Pediatrics November 1976
Table I. Clinical data, renal function, baseline serum values and radiographic diagnoses in children with chronic renal disease Renal function
Baseline serum values
Clearance ml/ rain 1.73m ~ Patient
Age
M.K.
10 4/12 11 8/12 12 9/12 3 6/12
G.I. F.R. A.H.
Calcium infusion
Glucagon injection
Radiographic diagnoses
Calcium Phosphates iPTH Calcium Phosphates iPTH Osteomalacia HyDerDaraDiagnosis [GFR PAH Urate TRP (mg/dl) (mg/dl) (pg/ml) (mg/dl) (mg/dl) (Dg/ml) or rickets thyroidism OU
28 ~
157
17
54
8.4
4.2
1,327
9.5
4.2
1,143
0
Mild
ATD
17~
85
7
27
7.9
6.0
1,515
7.6
5.8
1,534
Mild
Mild
CPN
841
303
12
77
9.4
5.1
133
8.9
5.0
201
0
0
HK
8~
-
14
36
10
2.5
342
9.5
7.1
2,404
Severe
Severe (parathyroidectomy) Severe (parathyroidectorny) Severe
J.B.
9 3/12
C
13"
-
45
39
8.5
3.8
375
7.9
Not done
430
Severe
T.C,
4 1/12
OU
38 ~
100
11
41
8.3
4.2
1,655
9.7
5.1
1,630
Severe
GFR = glomerular fiti'ation rate; PAH = para-aminohypurate; TRP = tubular reabsorption of phosphate; iPTH = immunoreactiveparathyroid hormone; OU = obstructive uropathy; ATP = asphyxiating thoracic dystrophy; CPN = chronic pyelonephritis; HK = hypoplastic kidneys; C = cystnosis.
in resumption of growth following renal transplantation be related to hyperparathyroidism induced or perpetuated by corticosteroids?
MATERIALS AND METHODS Our studies were performed in three groups of children. Group I included six children who had renal insufficiency but had not required hemodialysis. Group II included four children who were receiving hemodialysis regularly. Group III consisted of five children who were treated for seven episodes of acute renal transplant rejection. Studies in the first group were designed to establish whether there was autonomous function of the parathyroid glands. Those studies in the second group were designed to determine whether a high concentration o f ionized calcium in the dialysate solution would suppress circulating levels of immunoreactive parathormone. The studies in Group III were designed to determine if acute changes in circulating levels of calcium and i P T H occur after the administration of large doses of corticosteroids. The type of study and the potential risks were explained to the family of each child, and informed consent was obtained. The three study protocols were approved by the H u m a n Research Committee of St. Christopher's Hospital for Children. Group I (chronic renal insufficiency). The clinical features of the renal disease in these children are summa-
rized in Table I. Their concentrations of total serum calcium were elevated or lowered and the concurrent changes in serum levels of iPTH and inorganic phosphate monitored. In four children (M. K., G. I., F. R., A. H.) an attempt was made to lower the serum concentration of C a t by administering glucagon in a dose of 1 mg intravenously or 2 mg intramuscularly. Serum specimens were obtained prior to and at 15-minute intervals for two to five hours following injection of glucagon. In these four children and also in Patients J. B. and T. C., the serum concentration of Cat was increased by infusing calcium salts intravenously. The infusions of calcium salts were performed on the day following the glucagon study except in Patient A. H. (16 days after receiving glucagon). Infusions of inulin and para-aminohippurate were performed, and timed collections of urine and serum specimens were obtained to quantitate renal function. Subsequently, the equivalent o f 4 m g / k g / h o u r of elemental calcium was infused in the form of calcium gluceptate for four hours. Blood samples were obtained prior to, during the calcium infusion, and for periods of two to four and one-half hours afterward. Group II (hemodialysis). In four children, the changes in the serum levels of Cat, P~, and iPTH were determined over a period of five hours of hemodialysis. Simultaneous blood samples were drawn from the arterial and venous lines attached to the dialysis coil. The concentration of
Volume 89 Number 5
Parathyroid function in uremic children
757
T a b l e It. Clinical data a n d changes in B U N a n d creatinine values before a n d after dialysis; o n e - h a l f o f a new T r a v e n o l coil, ultraflo, was used for each child
Creatinine BUN (mg/dl) Patient
No. of hemodialyses
Diagnosis*
Age
Coil
W.T.
93
CGN
16 3/12
49
C.H.
11
CGN
10 2/12
19
M.L.
69
CPN
9 11/12
22
W,W.
13
CGN
12
28
1/2 UF 100 1/2 UF 60 1/2 UF 100 1/2 UF 100
8
l] Degree of renal osteodystrophy
66
42
11.8
Moderate
76
26
9.6
4.4
Severe
56
20
8.6
3.7
Severe
99
37
7.7
3.6
None
BUN = Blood urea nitrogen; UF = ultraflo; CGN = chronic glornerulonephritis; CPN = chronic pyelonephritis. T a b l e III. Clinical data a n d baseline serum values in children with renal transplants
Patient M.L.
A ge
Diagnosis
W.W. J.B. M.I.
9 9 12 9 17
6/12 ' 10/12 1/12 7/12 11/12
CPN CGN FN ATD
R.C.
15
1/12
CGN
Days r transplantation
Serum calcium (mg/dl)
Inorganic phosphate (mg/dl)
iPTH (pg/ml)
BUN (mg/dl)
Transplant 1, 54 Transplant 2, 8 22 28 368 369 262
7.6 9.0 8.9 8.5 9.6 10.2 9.8
3.4 2.6 4.9 3.4 4.0 3.5 4.3
1,918 716 258 606 246 119 1,000
58 35 22 44 19 21 19
Crealinine (mg/dl) 3.0 2.0 0.9 1.2 1.4 1.3 2.0
CPN = Chronic pyelonephritis; CGN = chronic glomerulonephritis; FN = familial nephritis; ATD = asphyxiating thoracic dystrophy. ionized calcium in the dialysate at the b e g i n n i n g o f dialysis was 7 to 8 m g / d l . T a b l e I | contains the clinical diagnosis o f each child, type of dialysis coil used, a n d the changes in serum levels o f urea nitrogen a n d creatinine that occurred during dialysis. Group Ill (post-transplantation studies). T h e age, diagnosis, n u m b e r o f days after transplantation, a n d p r e t h e r a p y serum levels of Cat, Pi, a n d i P T H in the five patients treated for t r a n s p l a n t rejection are listed in Table III. After o b t a i n i n g two samples o f p r e t r e a t m e n t blood 30 m i n u t e s apart, seven episodes of t r a n s p l a n t rejection were treated with a o n e - h o u r i n t r a v e n o u s infusion containing 20 m g / k g o f prednisolone. After completing the infusion, changes in serum concentrations of Cat a n d i P T H were d e t e r m i n e d at intervals o f one to two h o u r s for periods o f six to 12 hours. Procedure. In all three groups, the s e r u m was separated i m m e d i a t e l y from the red blood cells a n d frozen until analyzed. S t a n d a r d m e t h o d s for m e a s u r e m e n t o f levels of total serum calcium, 6 phosphates, 7 urea nitrogen, ~ creatinine/~ uric acid, TM inulin, H a n d P A H ~'-'were employed. T h e
duplicate d e t e r m i n a t i o n s of solute and iPTH were p e r f o r m e d in separate laboratories, each being u n a w a r e o f the other's results. All o f the d e t e r m i n a t i o n s for iPTH in any single Patient were p e r f o r m e d simultaneously. Levels of i P T H were d e t e r m i n e d by a r a d i o i m m u n o a s s a y described in detail elsewhere? ~ Using this assay, the m e a n value for iPTH concentration in 76 n o r m a l children from one to 18 years of age was 125 - 70 SD p g / m l . 13 The coefficient of variation f o u n d in multiple d e t e r m i n a t i o n s using serum from a patient with h y p e r p a r a t h y r o i d i s m was 10.7%? ~ T h e assay recognizes the antigenic site n e a r the a m i n o terminus.
RESULTS Group !. Glucagon injection.
Preinjection values for serum concentrations o f Cat, Pi, a n d iPTH are presented in Table I. A significant decrease in serum levels of Ca, and P, occurred within a n d persisted for 60 m i n u t e s in three of the four children (Fig. i). In the fourth child, n o c h a n g e in the concentration of Ca~ was seen until 240 minutes after
758
Gruskin et al.
The Journal of Pediatrics November 1976
21
1.8-"--~
9 MK /
~~
.16-
~176
2
1.0--
...... ~"................ "
l.u --i
I
..., ........ 9...................
............ 1 . . * ....... . 0
< >
0.8--
>
E
1.2--
, . " - - F.
~
'
2
"MTcKG
~
+
1.4
t - - ~ . ~
1.2--
0
iJ
z 0
§
~-J
+
.].
I.I--
t .0--
"**" TC " MK
1.2--
/[--
~MK ,*MK
1 . 0 . _ . ~ _ _ ~ . ~ - - - - ~ - ~
~ ....
~AH
~
us
1,0--
<
o.9
:E
,B
>
.-i
>
AN
FR
/~
0.9--
t
b" 1.4-~ 1
/
/
,,v r
2:) ,v
0.8--
us
Te
1.6--r-
GI
1.4--
MK
1.21.0
FR
r";L....
0.8 (3
I
I
I
I
I
I
I
1 0.2
Iol
I ol ~1 ~l ,::,1 I I
MINUTES AFTER G L U C A G O N Fig. 1. Relative changes in the serum levels of total calcium. phosphorusj and iPTH following administration ofglucagon. The ordinate is a time axis. Values shown on the abscissa indicate changes from control values which were obtained by dividing control values by subsequently obtained values at the stated intervals. Serum concentrations corresponding to control values for individual children are provided in Table I. the injection of glucagon. The ranges of m a x i m u m decreases for serum concentrations of Ca~ and P~ were from 0.2 to 1.3 mg/dl and 0.3 to 1.0 mg/dl, respectively. There were no changes in levels of iPTH during the first 60 minutes; however, during the n e x t 60 minutes, the serum level of iPTH increased by more than 20% in the three children whose serum concentration of Cat had fallen. Calcium infusion. In five of the six children with renal insufficiency, elevated serum levels of iPTH and depressed inulin and PAH clearances to less than 25% of normal values were noted (Table I). The percent of tubular phosphate reabsorbed in these five patients was depressed, During each infusion of calcium, the serum concentrations of Ca~ increased, while serum levels of iPTH fell. Serum concentrations of iPTH decreased by
L ~'~
,v c A , c , u M 4mg/kg/hr
.I "7
MINUTES FROM ONSET OF CALCIUM INFUSION Fig. 2. Relative changes in serum values of calcium, phospl~orus, and iPTH following intravenous infusions of calcium gluceptate (4 mg/kg/hr for 4 hours). The plotting methodology is similar to that of Fig. 1. Serum concentrations corresponding to control values for individual children are provided in Table 1.
more than 60% in all patients (Fig. 2), and in three attained normal levels. However, serum levels of {PTH returned to preinfusion levels within two hours after discontinuation of intravenous calcium salts. Serum concentrations of P~ tended to rise during the calcium infusion. Group I 1 . W h e n dialyzed against a dialysate containing an ionized calcium concentration of 7 to 8 mg/dl, serum concentrations of Ca~ increased and levels o f i P T H and P~ decreased during hemodialysis (Table IV). Ca~ concentrations in the venous blood lines (coil to body) were always higher than in the arterial lines. Calcium, then, was always moving from dialysate to child. The similarity between
Volume 89 Number 5
Parathyroid function in uremic children
75 9
Table IV. Changes in arterial and venous values during hemodialysis
Hours ofhemoda@sm Laboratory examination
Patient W.T.
Serum calcium (mg/dl) Inorganic phosphate (mg/dl)
C.H.
iPTH (pg/ml) Serum calcium Phosphate
M.L.
iPTH Serum calcium Phosphate
W,W.
iPTH Serum calcium Phosphate
Source
1/4
1
3
Arterial Venous Arterial Venous Arterial Arterial Venous Arterial Venous Arterial Arterial Venous Arterial Venous
8.9 9.0 5.7 5.9 ~0 9.0 10.0 6.5 6.4 553 9.8 10.6 2.9 2.3 283 7.4 8.3 8.2 6.0 1079
9.0 11.3 5.5 4.0 285 9.8 10.6 5.7 4.6 503 11.0 11.6 2.7 2.1 233 8.1 9.1 7.6 5.3 969
9.4 11.4 5.3 4.8 253 10.0 11.0 5.2 4.3 448 11.1 12.0 2.7 1.9 230 8.7 9.6 6.9 4.6 536
Arterial Venous Arterial Venous
iPTH
the concentrations ofiPTH in the arterial and venous lines suggests that hemodialysis does not remove iPTH from the serum. Two children attained normal serum levels of iPTH. No correlation between the clinical or radiographic severity of renal osteodystrophy and serum levels of iPTH was found in the children in Group I and those in Group II. Patients A. H. and J. B. (Group I) had subtotal parathyroidectomies within one month following these studies. The level of circulating iPTH in Patient A. H. fell from 2,404 to 342 pg/ml during in-hospital therapy with Basaljel, a phosphate-binding aluminum salt. Although each child attained normal serum levels of iPTH during the calcium infusion, the lack of patient a n d family compliance with conservative medical management necessitated surgery. Each child had radiographic evidence of severe hyperparathyroid bone disease. The weights of the parathyroid tissue removed from Patients A. H. and J. B. were 8.0 and 4.5 times, respectively, that expected in the normal child. TM Histologic examination revealed diffuse parathyroid hyperplasia. Group IIl. The baseline information relative to this group is summarized in Table III. Serum concentrations of Cat decreased following six of the seven one-hour intravenous infusions containing 20 mg/kg of prednisolone intended to reverse renal transplant rejection (Fig. 3). The range of maximum depression of serum concentrations of Cat was 0.2 to 1.4 mg/dl. Specimens of serum for
I
i
5 9.8 13.0 5.0 3.6 240 10.2 11.6 5.0 3.9 390 12.4 12.8 2.4 1.8 193 9.1 10.1 6.4 4.0 328
determining Cat were unavailable from the seventh study. Serum concentrations of Cat remained depressed for six to 12 hours following the infusion of prednisolone in five of the six studies. Serum levels of iPTH increased by at least 50% in five of the seven studies. A consistent change in the serum level of P~ was not observed. DISCUSSION Suppression of serum levels of iPTH toward normal could regularly be achieved in our patients by elevation of the serum concentration of Cat, whether by infusion of calcium salts as in Group I or by hemodialysis against a dialysate with a high concentration of ionized calcium in Group II. This suggests that functional autonomy of the parathyroid gland did not exist in any of these uremic children. Calcium infusion resulted in increases of serum Cat concentration of at least 25% and reduction of levels of iPTH of more than 60% in all five of the uremic children in Group I, irrespective of the degree of severity of their renal osteodystrophy. Roof and coworkers, ~5 on the other hand, found that intravenous infusion of calcium salts suppressed serum levels of iPTH with certainty only in 14 uremic patients who did not have roentgenographic evidence of renal'osteodystrophy. In 17 patients with radiographically apparent bone disease, higher preinfusion levels of iPTH and smaller reductions of iPTH.concentrations during infusion of calcium salts were observed. In fact, levels of iPTH did not decrease in
760
Gruskin et al.
The 4~ournalof Pediatrics November 1976
1.05-~
"> :
"< 89
.........
.85 ~' O
~ U
.80
2.5
.J,
ILl ,=a
t
2.0--
/"~
...--'"~'""~~
ww
.,( > zE I,LI
1.0-- ,..'2".
-
"--M~
................................... Fie
.75
I 0
( 2
I
I 4
I
( I I 6 8
I
I I I i0 12
HOURS AFTER INTRAVENOUS PREDNISOLONE Fig. 3. Relative changes in serum values of calcium and iPTH following intravenous infusions of prednisolone (20 mg/kg). The plotting method is similar to that of Fig. 1. Serum concentrations corresponding to control values for individual children are provided in Table IlI.
five of their patients. A difference between Roof and associates' studies and the present one is that we infused a greater amount of calcium: 16 mg/kg/4 hours of elemental calcium equivalent compared to 10 mg/kg/3 hours (26 patients) 1~ or 15 mg/kg/4 hours (15 patients).l~ Lack of parathyroid autonomy in uremic children was not so evident when reduction of serum Cat concentration was used to stimulate PTH secretion. Glucagon, the agent used in Group I to lower serum concentrations of Cat, acts by increasing the uptake of calcium by bone and does not require the presence of either the thyroid gland or kidney to effect its change. 16 17Elevation of serum levels ofiPTH occurred in only three of the four patients studied after administration ofglucagon. The fourth patient, A. H., had diffuse parathyroid hyperplasia. These findings in addition to previous studies showing that serum concentrations of iPTH increase in patients with parathyroid adenoma following EDTA-induced reduction of serum Cat TM indicate that pharmacologic maneuvers which lower serum calcium may not differentiate autonomous from suppressible parathyroid function. Our observations have several therapeutic implicationsi In children with renal insufficiency who are not receiving hemodialysis, parathyroid gland function is not autonomous and therefore vigorous, persistent medical therapy should limit the degree of renal osteodystophy. However,
this .goal might be an unrealistic expectation in some children because of their failure to adhere to rigid medical and dietary regimens. Patients A. H. and J. B. required subtotal parathyroidectomy for Control of renal osteodystrophy in spite of our being able to suppress their serum iPTH to normal values by the intravenous infusion of calcium salts and/or adequate reduction of serum Pi concentrations with oral aluminun~ salts. Levels of iPTH were also able to be suppressed to normal values in the presence of a large mass of hyperplastic parathyroid tissue in these children. These observations are at variance with those of others who were unable to inhibit parathormone synthesis in animals in which the mass of parathyroid tissue had been artifically increased. 1~.... The studies in Group I I as well as others 2~demonstrated that when hemodialysis is performed using a dialysate concentration of ionized calcium greater than 7 mg/dl, transient decreases in levels of iPTH during dialysis and concurrent elevations of serum concentrations of Cat occur. Such observations suggest that hemodialysis against a high dialysate concentration of ionized calcium should be effective therapy for renal bone disease. .... Patients dialyzed with a high dialysate concentration of calcium may have normal sized parathyroid glands at autopsyr Some investigators, however, feel that the use of high concentrations of calcium in the dialysate does not retard progression of osteodystrophy2 ~' '-'~Since the use of a high concentration of calcium in the dialysate transiently suppresses parathyroid function, the reason for the differences between these opinions may be related to the type of therapy used to suppress parathyroid function between dialyses. In the children of Groups I and II there was no correlation of serum levels of iPTH with the extent of radiographically demonstrable renal osteodystrophy. Potter and co-workers '-'~have also shown that the degree of renal bone disease in children correlates with the duration of renal insufficiency rather than with the serum level of iPTH. Metabolic bone disease in children with renal insufficiency may cause severe skeletal deformities and may also be one of the more important factors contributins to growth retardation in these children. -~4Although autonomy of the parathyroid gland only rarely occurs as part of the spectrum of renal disease, medical therapy for secondary hyperparathyroidism may fail in all children to control the progression of their osteodystrophy, and parathyroidectomy may be necessary. Relatively few children have been reported to have had subtotal or total parathyroidectomy for renal osteodystrophy.-" '-'~In general, parathyroidectomy has resulted in healing of bone fractures, and the growth rate of these children has improved.'-'
Volume 89 Number 5
The acute response of serum Ca t and iPTH levels to corticosteroid administration has not previously been reported in patients receiving large doses o f prednisolone (20 mg/kg) for the treatment of transplant rejection. Following renal transplantation the doses of corticosteroids in relation to body weight for control of rejection are much greater than doses used for the therapy and differential diagnosis of hypercalcemia. ~ Our studies suggest that the administration of sufficient quantities of corticosteroids may influence both the serum levels of Ca t and iPTH. Popovtzer and associates 27 reported that, following renal transplantation, the levels of serum calcium are inversely related to the total dose of prednisone and that, w h e n the dose of prednisone is lowered, serum levels of Cat often increase. Corticosteroids may also increase levels of i P T H by 72% without changing levels of Ca~. ~8 The changes in Cat in patients following predniso!one infusions occurred too rapidly to be attributed to the known capacity o f corticosteroids to decrease calcium transport across the bowel. -~'~Changes in serum levels of Pi were not consistent and cannot explain the decreases in serum levels of Ca t in our patients. Corticosteroid administration also does not cause hypocalcemia by lowering serum protein concentrations? ~ Although hypocalcemia and increases of iPTH both occur in association with acute reduction of renal function, ~ our observations cannot be explained by loss of renal function associated with transplant rejection episodes. In some of the patients, further reduction of renal function did not occur, while in others anti-rejection therapy was instituted prior to measurable change in glomerular filtration rate. Steroid-induced decreases in serum Cat concentration also cannot be explained by an increased rate of excretion o f calcium, since calcium excretion decreases after the rapid intravenous administration of high doses of prednisoneY-' The mechanism for the reduction of serum C.a t may possibly reflect increases in circulating glucagon related to chronic steroid therapy. Oral prednisone at a dose of 40 to 60 m g / d a y for three days in normal adults increased fasting serum levels of glucagon, but the intravenous infusion of I00 mg of prednisolone over five minutes did not? 3 Finally, a reduction in the serum concentrations of Cat may be due to steroid interference with PTH-induced calcium release from bone? ~ These studies demonstrate a reduction in serum levels of Cat and elevation in i P T H following massive individual doses of intravenous corticosteroids. They suggest that the complex interplay of corticosteroids, glucagon, and parathormone may contribute to depression of growth in children receiving chronic corticosteroid therapy and to delay in resumption of growth following renal transplantation. The onset of growth following transplantation is
Parathyroid function in uremic children
76 1
related to the amount o f corticosteroid ingested during the post-transplant period? The authors express their appreciation to the nursing staffs of the Hemodialysis Unit and Clinical Research Center of St. Christopher's Hospital for Children for their help in performing these studies, to Deborah Troyanosky, renal technologist, to Drs. V. C. Vaughan III and L. Hiner for reviewing the manuscript, and to Sandra Turner for her secretarial assistance. REFERENCES
1. Fine RN, Isaacson AS, Payne V, and Grushkin CM: Renal osteodystrophy in children. The effect of hemodialysis and renal homotransplantation, J PEDIArR 80:243, 1972. 2. Firor HV, Moore ES, Levitsky LK, and Galvez M: Parathyroidectomy in children with chronic renal failure, J Pediatr Surg 7:565, 1972. 3. Popowniak KL, Esselstyn CB Jr, and Nakamoto S: Parathyroidectomy for the treatment of renal osteodystrophy and tertiary hyperparathyroidism: Progress report, Surg Clin North Am 54:325, 1974. 4. Fournier AE, Arnaud CD, Johnson W J, Taylor WF, and Goldsmith RS: Etiology of hyperparathyrgidism and bone disease during chronic hemodialysis, J Clin Invest 50:599, 1971. 5. Hoda Q, Hasinoff DJ, and Arbus GS: Growth following renal transplantation in children and adolescents, Clin Nephrol 3:6, 1975. 6. Conboy J, Davis M, and Gott JD: Statistics of a fluorometric calcium determination, Am J Clin Pathol 53:196, 1970. 7. Gomori G: A modification of the colorimetric phosphorus determination for use with the determination of blood urea, Clin Chem 11:624, 1965. 8. Marsh WH, Fingerhut B, and Miller H: Automated and manual direct methods for the determination of blood urea, Clin Chem 11:624, 1965. 9. Bonsnes RW, and Taussky HH: On the colorimetric determination of creatinine by the Jaffe reaction, J Biol Chem 158:581, 1945. 10. Caraway WT: Determination of uric acid in serum by a carbonate method, Am J Clin Pathol 25:840, 1955. 11. Walser M, Davidson DG, and Orloff J: The renal clearance of alkali-stable inulin, J Clin Invest 342:1520, 1955. 12. Smith HW, Finkelstein N, Aliminosa L, Crawford B, and Grader M: The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man, J Clin Invest 23:388, 1945. 13. Root A, Gruskin A, Reber RM, Stopa A, and Ducker t G: Serum concentrations of parathyroid hormone in infants, children and adolescents, J PEDIATR85:329, 1974. 14. Gilmour JR, and Martin WJ: The weight of the parathyroid glands, J Pathol Bact 44:431, 1937. 15. Roof BS, Piel CF, Rames L, Potter D, and Gordon GS: Parathyroid function in uremic children with and without osteodystrophy, Pediatrics 53:404, 1974. 16. Williams GA, Bowser EM, and Henderson WJ: Mode of hypocalcemic action of glucagon in the rat, Endocrinology 85:537, 1969. 17. ~fanzer FS, Kennedy JW, and Talmage RV: A comparison of the effects of thyrocalcitonin and glucagon on plasma
762
18.
19.
20.
21.
22.
23.
24. 25. 26. 27.
Gruskin et aL
calcium and phosphate, Proc Soc Exp Biol Med 133:500, 1970. Murray TM, Peacock M, Powell D, Monchik JM, and Ports JT Jr: Non-autonomy of hormone secretion in primary hyperparathyroidism, Clin Endocrinol 1:235, 1972. Gittes RF, and Rudde IC: Experimental hyperparathyroidism from multiple isologous parathyroid transplants. Homeostatic effect of simultaneous thyroid transplants, Endocrinology 78:1015, 1966. Gittes RF, and Radde IC: Experimental model of hyperparathyroidism: Effect of excessive numbers of transplanted isologons parathyroid glands, J Urol 95:595, 1966. Goldsmith RS, Forxzyfer J, Johnson W J, Fournier AE, and Arnaud CD: Control of secondary hyperparathyroidism during long term hemodialysis, Am J Med 50:692, 1971. Potter DK, Wilson C J, and Ozonoff MB: Hyperparathyroid bone disease in children undergoing longcterm hemodialysis treatment with vitamin D, J PEDIATR 85"60, 1974. Eastwood JB, Bordier J, and DeWardener HE: Some biochemical, histological, radiological and clinical features of renal osteodystrophy. Kidney lnt 4:128, 1973. Stickier GB, and Bergen BJ: A review: Short stature in renal disease, Pediatr Res 7:978, t973. Ogg CS: Parathyroidectomy in the treatment of secondary renal hyperparathyroidism, Kid lnt 4:168, 1973. Dent CE, and Watson L: The hydrocortisone test in primary and tertiary hyperparathyroidism, Lancet 2:662, 1968. Popovtzer MM, Geis WP, and Starzl TE: Hyperparathyroidism after kidney homotransptantation. 1. Relation to homograft function, in Hioco D, editor: International
The Journal of Pediatrics November 1976
28.
29.
30.
31.
32.
33.
34.
Symposium on kidney and calcium, Sandoz Editions, les trios epis, Paris, December 14-17, 1972, Ruel-Malmaison, p 145. Fucik RF, Kukreja SC, Haryis GD, Bauser EN, Henderson W J, and Williams GA: Effect of glucocorticoids on function of the parathyroid glands in man, J Clin Endocrinol Metab 40:152, 1975. Favns MJ, Kimberg DV, Miller GN, and Gershon E: Effects of cortisone administration in the metabolism and localization of 25-hydroxycholecalciferal in the rat, J Clin Invest 52:1328, 1973. Williams GA, Peterson WC, Bowser EN, Henderson W J, Hargis GK, and Martinez N J: Interrelationship of parathyroid and adrenocorticat function in calcium homeostasis in the rat, Endocrinology 95:707, 1974. Massry SG, Coburn JW, Lee DBN, Kleeman J J, and Kleeman CR: Skeletal resistance to parathyroid hormone in renal failure, Ann Intern Med 78:357, 1973. Popovtzer MM, Pinggera WG, Robinette J, Holmes JH, Holgrimson CG, and Starzl TE: Acute renal response to large dose of intravenous prednisolone in kidney homograft recipients and in normal subjects, J Lab Clin Med 78:39, t974. Wise JK, Hendler R, and Felig P: Influence of glucocorticoids in glucagon secretion and plasma amino acid concentrations in man, J Clin Invest 52:2774, 1973. Eliel LP, Thomsen C, and Chanes R: Antagonism between parathyroid extract and adrenal cortical steroids in man, J Clin Endocronol 25:457, 1965.