- Email: [email protected]
Effectiveness of 1 α-hydroxyvitamin D3 in children with renal osteodystrophy associated with hemodialysis
May 1977
820
TheJournalofPED1ATRICS
Effectiveness of i a-hydroxyvitamin D3 in children with renal osteodystrophy associated with hemodialysis Two children who were receiving maintenance hemodialysis were treated with 1 to 4 ~g/day of I ahydroxyvitamin D:~for 500 to 700 days, respectively. Sequential parathyroid hormone levels and radiologic evaluations showed considerable improvement in one patient. The second patient initially responded with healing of the bone disease. Subsequent deterioration may be related either to medical noncompliance and/or interference by diphenylhydantoin in the subsequent hepatic 25-hydroxylation of l a-OH-D~.
James C. M. Chan, M.D.,* Washington, D. C., Susan B. Oldbam, Ph.D.,
Los Angeles, Calif., and Hector F. DeLuea, Ph.D., Madison, Wis.
IT IS NOW WELL ACCEPTED that the kidney activates 25-hydroxyvitamin D 3 to the hormone, l-a-25-dihydroxyvitamin D 3. Impaired activation in uremia contributes to the development of renal osteodystrophy. Recently, we published the results of the effects of a potent analog, l-ahydroxyvitamin D3 in eight patients with renal osteodystrophy administered for up to 260 days? Mineral balance studies showed that during treatment with 1 to 3/~g of 1 aOH-D3, administered orally, net gastrointestinal absorp-
From the Department of Nephrology, Children's Hospital National Medical Center and Department of Child Health and Development, George Washington University School of Medicine; the Department of Medicine, University of Southern California School of Medicine; and the Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin. Supported by grants RR-00284, RR-05515, RR-86, H S M 110-71-270, AM-14881, AM-15512 and AM16081from the National Institutes of Health, the Department of Health, Educationand Welfare, the Ruth and ArnoM Orleans Kidney Research Fund. Presented in part in the American Federation of Clinical Research, Boston, January 1975 and the lOth International Congress of Nutrition, Kyoto, August 1975. *Reprint address: Bldg 10, Rm 8N214, NHLBL Section on Steroid and Mineral Metabolism, National Institutes of Health, Bethesda, MD 20014.
Vol. 90, No. 5, pp. 820-824
don of calcium was enhanced, resulting in improved calcium balance. 1In view of the limited supply of I a-OHD3, prolonged studies of up to 700 days were confined to two children who were receiving maintenance hemodialysis. The clinical, biochemical, and radiographic changes associated with their extended treatment serves as the basis of this report. MATERIALS
AND METHODS
1 c~-OH-D3 was chemically synthesized from cholesterol at the University of Wisconsin5 It was dissolved in propylene glycol to give a concentration of 2/.tg/ml and stored at - 2 0 ~ under nitrogen in tightly sealed vials. A dosage of 0.5 to 3.0 #g was administered orally at bedtime.
Abbreviations used I-a-OH-D3: l-a-hydroxyvitamin D3 1-a-25-(OH)z-Ds: 1-a-25-dihydroxyvitamin D iPTH: immunoreactive parathyroid hormone PTH: parathyroid hormone
Two girls, aged 12 and 15 years old, receiving maintenance hemodialysis secondary to end-stage renal failure were studied. In the first child, the primary renal disease was focal segmental glomerulosclerosis which was diagnosed and followed for four years and six months prior to
Volume 90
Hydroxyvitamin D~ with osteodystrophy and hemodialysis
821
Number 5
Izg/day 31-l ~;
~
10 '~
31
9
B
- 10 -9
.
-E
7 ~
-7
i,,t,, '~' il ~.~
',''~
3oo
~~~ < 091-
ll t u i l
,30o
~
]/
150 NORMAL
9000 -
- 9000 _
~,
o.
." soo0 %~~o~ ~" ~ 3000 ~ ~ -~ ~ %.o
oe
2 Eoo0 3000
NORMAL
0
0
100
200
300
400
500
DAYS OF TREATMENT Fig. 1. Biochemical data during long-term (500 days) administration of 1 a-OH-D3 in Patient 1,
initiation of hemodialysis when the serum creatinine reached 11.6 mg/dl, coincidental with established clinical criteria for severe irreversible end-stage renal failure:'; treatment with 1 c~-OH-D~ was started nine months after she had been on maintenance hemodialysis at which time clinical evidence of renal osteodystrophy (elevated parathyroid hormone and alkaline phosphatase levels and radiologic changes) had become apparent.' The primary renal disease in the second child was recurrent urinary tract infections and obstructive uropathy, the duration of follow-up at renal clinic was five years prior to maintenance hemodialysis. The predialysis serum creatinine was 13.2 mg/dl and the manifestations of renal osteodystrophy was present.' Treatment with I a-OH-D:~ was started concurrent with initiation of hemodialysis. Diphenylhydantoin 200 mg/day was also given to this patient, beginning on day 33 because of the recurrence of an idiopathic seizure disorder. The patients were dialyzed three times a week for four to six hours on the Ultra-Flo II disposable coil dialyzer. The calcium concentration in the dialysate was 6.0 mg/dl; magnesium concentration was 1.5 mEq/dl. Predialysis serum calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone levels were measured every second to fourth week. Roentgenograms of bones were obtained at regular intervals. Dietary reslric-
Fig. 2. Remineralization of the distal end of the left clavicle in Patient 1 showing resorption prior to treatment and improvement at 185 and 456 days. tions and the dosage of calcium supplement and phosphate-binding gel as previously described ~ remain the same throughout the study period. Radioimmunoassay of parathyroid hormone was performed according to the method of Arnaud and associates:~ The antiserum used, AS2-1/32, was obtained from Burroughs-Wellcome Laboratories, London, U.K. This antiserum has been previously shown to have immunologic specificity directed primarily toward the aminoterminal region of the PTH molecule.; The reference standard used was bovine PTH obtained from the Medical Research Council, Division of Biological Standards, National Institute for Medical Research, London, U.K. (code No. 71/324). The observed normal values were less than 400 pg/ml. Serum calcium, inorganic phosphorus, and alkaline phosphatase activity were measured by standard methods previously described? The study was approved by the Research Committee of the institution and informed consent obtained for each patient. RESULTS Biochemical data in Patient 1 are summarized in Fig. 1. The daily dosage of orally administered 1 a-OH-D3 were sequentially increased from 1 to 3 #g over the first 120
8 22
Chan,Oldham, and DeLuca
The Journal qf Pediatrics May 1977 e~o j GIVEN AFTER JEACH
...j
~./.g/day 4~ t,j
. . . . .
.
.
.
.
.
.
DIPHENYLHIt :E
~-
Z~ .a< ~.~--
NORMAL a.
O ~ Zw
=
E
NORMAL 0
loo
200
300
DAYS OF
400
soo
800
700
TREATMENT
Fig. 3. Biochemical data during long-term (700 days) administration of 1 a-OH-D3 in Patient 2. Interrupted lines indicate periods of medical noncompliance. days and maintained at 3 t~g/day for the next 120 days until hypercalcemia of 11 mg/dl (at 240 days) dictated a gradual reduction over the next 160 days to 1 ~g/day. The plasma iPTH began to show a definite downward trend from the ninetieth day of treatment in conjunction with plasma calcium increasing to normal levels. By the two hundred fortieth day, the iPTH was 19% of the pretreatment levels and was maintained at that level despite decreased dosage of 1 a-OH-D:, to 1 /~g/day. The plasma alkaline phosphatase returned to normal by two hundred fortieth day, and remained so for the rest of the study. The plasma phosphate failed to show a consistent trend. The radiologic changes observed with 1 a-OH-D~ therapy in Patient 1 are shown in Fig. 2. She developed persistent left shoulder pain three months prior to therapy and resorption of the distal end of the clavicle was documented in the pretreatment roentgenogram (Fig. 2). Evidence of healing was present within 185 days and continued improvement was maintained at 456 days. In addition, remineralization was associated with rapid relief of the left shoulder pain. Biochemical data in Patient 2 are summarized in Fig. 3. The daily dosage of orally administered 1 a-OH-D~ were serially increased from 1 to 4 #g. In addition, from the thirty-third day of therapy, she began receiving diphenylhydantoin (200 rag/day orally) because of a seizure
disorder. Plasma iPTH initially decreased to 75% of pretreatment levels at 90 days, then rose again to values which were even higher than pretreatment levels. There was no apparent correlation between plasma iPTH and plasma calcium concentrations, which were in the low normal range throughout most of the study period. Plasma phosphate levels increased, and alkaline phosphatase levels remained elevated.. Segmental roentgenograms of the left index finger from the same patient are shown in Fig. 4. There was advanced subperiosteal erosion of the distal phalanx prior to therapy. Remineralization and appearance of the distal tuft was apparent after 45 days of therapy, with further improvement at 153 days. The final roentgenogram, taken at 305 days of treatment, showed deterioration. On the five hundred sixtieth day, medical noncompliance was documented and the schedule was changed to 8 ~g grams after each hemodialysis to ensure medical compliance. She also admitted to noncompliance between 150 to 300 days. DISCUSSION The remarkable advancement in the past decade in defining the metabolic pathways and functions of vitamin D metabolites have clarified our understanding of the pathophysiology of renal bone disease and vitamin D resistant states. Short-term studies by Brickman and associates ~ for less than two weeks, with up to 2.7 ~g/day of the kidney hormone, 1-a-25-(OH)~D3, in four uremic adults, resulted in improved intestinal absorption of calcium and increased plasma calcium levels. Similar results were obtained by Chan and associates I in eight patients, using a synthetic analog, 1-a-OH-D3, at oral dosages of 1 to 4 #g/ day for up to 260 days. In addition, a significant reduction of iPTH levels during therapy was demonstrated.' Chalmers and associates, l~ Peacock and colleagues," Hirooka and associates, ~ and Balson and coworkers ':' independently documented the short-term action of 1-a-OH-D:~ directly on bone and intestine, but parathyroid activity was not reported. The lag period between administration of I-a-OH-D.~ and roentgenographic healing of rickets (45 to 185 days) in our cases is longer than that reported by Hirooka and associates ~2and Henderson and coworkers. ~ This may be related to variability of absorption of the vitamin analog or other yet undefined factors. The present study demonstrates that prolonged treatment with small amounts of 1-a-OH-D:, orally for up to 700 days can ameliorate the renal osteodystrophy as evidenced by sustained reduction of plasma iPTH levels, plasma alkaline phosphatase, radiologic evidence of healing, and subjective alleviation of bone pain. The complication of hypercalcemia is easily counteracted by reduc-
Volume 90 Number 5
Hydroxyvitamin D:~ with osteodystrophy and hemodialysis
823
Fig. 4. Radiologic changes in the right index finger of Patient 2 showing resorption of distal tuff prior to treatment and
improvement at 45 and 153 days. Deterioration and resorption of the distal tuft recurred at 305 days. tion of dosage and is not as severe as that described by Brickman and associates.~'using 1-a-25-(OH)~-D3. The less successful results in our second patient may, in part, be attributed to the anticonvulsant therapy she was receiving during the study period. A study on institutionalized mentally retarded children showed those receiving phenobarbital or diphenylhydantoin had lower concentration of 25-OH-vitamin D in their plasma.':' This, as well as other studies, suggests an interference by anticonvulsant medication on the normal metabolism of vitamin D. Since it appears that I-a-(OH)-D~ must be hydroxylated to Ia-25-(OH)~D:~ before it is physiologic active, TM factors which alter the formation of 25-OH-D~ from vitamin D:~ might be expected to alter the utilization of this synthetic analog. However, since evidence for increased bone mineralization in this patient was seen during the initial 153 days of therapy, despite concomitant anticonvulsant medication, the subsequent deterioration is more likely attributable to her medical noncompliance, which applies not only to the Ia-OH-D:. but extends to poor compliance of all dietary restrictions, as well as calcium supplementations, phosphate-binding gel, and" the diphenylhydantoin. Serum diphenylhydantoin levels were not measured so that consistent intake of this drug was not established. The sustained low levels of iPTH in Patient l for a period of 220 days (day 180 to 400, Fig. l) was related
primarily to the use of 1 a-OH-D3 and most likely contribute to the development of two episodes of hypercalcemia at 270 and 365 day s of therapy, respectively. However, the sustained correction of hypocalcemia via the hemodialysis procedures must be recognized. In conclusion, it should be emphasized that there are multiple factors contributing to the development of renal osteodystrophy? ............. The impaired production of the kidney hormone, 1-a-25-(OH)2D3, is only one of the major factors. The present study does, however, add further support to the efficacy and relative lack of complications in the prolonged use over two years of an analog of the active vitamin D metabolite in the treatment of renal osteodystrophy in patients who are receiving maintenance hemodialysis. The experience also points to the importance of iPTH levels as indices of adequacy of dosage levels. REFERENCES
1. Chan JCM, Oldham SB, Holick MF, and DeLuca HF: 1 ahydroxyvitamin D~ in chronic renal failure: A potent analogue of the kidney hormone, 1,25-dihydroxycholecalciferok JAMA 234:47, 1975. 2. Holick MF, Semmler EJ, Schnoes HK, and DeLuca HF: 1 a-hydroxy derivative of vitamin D3: A highly potent analog of la, 25-dihydroxyvitamin D3, Science 180:190, 1973. 3. Chan JCM, and Parrish AE: Maintenance pediatric hemodialysis: Principles and techniques, Clin Proc Child Hosp Natl Med Ctr 30:214, 1974.
82
49
5~
6
7 8 9
10
ll
,an, Oldham, and DeLuca
CM: Renal osteodystrophy in children, Clin Pediatr 1976. 7M: Dietary management of renal failure in infants 9 ;dren: principle of nutritional therapy and some ~,~ive diets, Clin Pediatr 12:707, 1973. , CD, Tsao HS, and Littledike ET: Radioimmuof human parathyroid hormone in serum, J Clin ,,'.~:21, 1971. and Singer FR: Radioimmunoassay for human :old hormone, Clin Chim Acta 54:161, 19749 9 M: The effect of milk formulae on acid balance, .~:~ab 16:140, 1974. .n AS, Coburn JW, and Norman AW: Action of ~'droxycholecalciferoL a potent, kidney-produced ~te of vitamin D~ in uremic man, N Engl J Med 1972. TM, Hunter JO, Davie MW, et al: 1 alpha,.holecalciferol as a substitute for the kidney 1,25-dihydroxycholecalciferol in chronic renal ~mcet 2:696, 1973. M, Callagher JC, and Nordin BEC: Action of l
The Journal of Pediatrics May 1977
12.
13.
14.
15.
16.
alpha-hydroxyvitamin D3 on calcium absorption and bone resorption in man, Lancet 1:385, 1974. Hirooka M, Wako H, Kaneko C, Ishikawa M, Sasaki S, and Suda T: Curative effects of 1 a-hydroxycholecalciferol on calcium metabolism and bone disease in patients with chronic renal failure, J Nutr Sci Vitaminol 21:277, 1975. Balsan S, Gatabedian M, Gorgniard R, Holick MF, and DeLuca HF: 1,25-dihydroxyvitamin D3 and l a hydroxyvitamin D3 in children: Biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance, Pediatr Res 9:586, 1975. Henderson RG, Russell RGG, Ledingham JFF, et al: Effects of 1,25 dihydroxycholecalciferol on calcium absorption, muscle weakness and bone disease in chronic renal failure, Lancet 1:379, 1974. Tolman KG, Jubiz W, Sannella JJ, Madsen JA, Belsey RE, Goldsmith RS, and Freston JW: Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children, Pediatrics 56:45, 1975. DeLuca HF: Proceedings of 1 lth European symposium on calcified tissue (1975) (in press).
820
TheJournalofPED1ATRICS
Effectiveness of i a-hydroxyvitamin D3 in children with renal osteodystrophy associated with hemodialysis Two children who were receiving maintenance hemodialysis were treated with 1 to 4 ~g/day of I ahydroxyvitamin D:~for 500 to 700 days, respectively. Sequential parathyroid hormone levels and radiologic evaluations showed considerable improvement in one patient. The second patient initially responded with healing of the bone disease. Subsequent deterioration may be related either to medical noncompliance and/or interference by diphenylhydantoin in the subsequent hepatic 25-hydroxylation of l a-OH-D~.
James C. M. Chan, M.D.,* Washington, D. C., Susan B. Oldbam, Ph.D.,
Los Angeles, Calif., and Hector F. DeLuea, Ph.D., Madison, Wis.
IT IS NOW WELL ACCEPTED that the kidney activates 25-hydroxyvitamin D 3 to the hormone, l-a-25-dihydroxyvitamin D 3. Impaired activation in uremia contributes to the development of renal osteodystrophy. Recently, we published the results of the effects of a potent analog, l-ahydroxyvitamin D3 in eight patients with renal osteodystrophy administered for up to 260 days? Mineral balance studies showed that during treatment with 1 to 3/~g of 1 aOH-D3, administered orally, net gastrointestinal absorp-
From the Department of Nephrology, Children's Hospital National Medical Center and Department of Child Health and Development, George Washington University School of Medicine; the Department of Medicine, University of Southern California School of Medicine; and the Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin. Supported by grants RR-00284, RR-05515, RR-86, H S M 110-71-270, AM-14881, AM-15512 and AM16081from the National Institutes of Health, the Department of Health, Educationand Welfare, the Ruth and ArnoM Orleans Kidney Research Fund. Presented in part in the American Federation of Clinical Research, Boston, January 1975 and the lOth International Congress of Nutrition, Kyoto, August 1975. *Reprint address: Bldg 10, Rm 8N214, NHLBL Section on Steroid and Mineral Metabolism, National Institutes of Health, Bethesda, MD 20014.
Vol. 90, No. 5, pp. 820-824
don of calcium was enhanced, resulting in improved calcium balance. 1In view of the limited supply of I a-OHD3, prolonged studies of up to 700 days were confined to two children who were receiving maintenance hemodialysis. The clinical, biochemical, and radiographic changes associated with their extended treatment serves as the basis of this report. MATERIALS
AND METHODS
1 c~-OH-D3 was chemically synthesized from cholesterol at the University of Wisconsin5 It was dissolved in propylene glycol to give a concentration of 2/.tg/ml and stored at - 2 0 ~ under nitrogen in tightly sealed vials. A dosage of 0.5 to 3.0 #g was administered orally at bedtime.
Abbreviations used I-a-OH-D3: l-a-hydroxyvitamin D3 1-a-25-(OH)z-Ds: 1-a-25-dihydroxyvitamin D iPTH: immunoreactive parathyroid hormone PTH: parathyroid hormone
Two girls, aged 12 and 15 years old, receiving maintenance hemodialysis secondary to end-stage renal failure were studied. In the first child, the primary renal disease was focal segmental glomerulosclerosis which was diagnosed and followed for four years and six months prior to
Volume 90
Hydroxyvitamin D~ with osteodystrophy and hemodialysis
821
Number 5
Izg/day 31-l ~;
~
10 '~
31
9
B
- 10 -9
.
-E
7 ~
-7
i,,t,, '~' il ~.~
',''~
3oo
~~~ < 091-
ll t u i l
,30o
~
]/
150 NORMAL
9000 -
- 9000 _
~,
o.
." soo0 %~~o~ ~" ~ 3000 ~ ~ -~ ~ %.o
oe
2 Eoo0 3000
NORMAL
0
0
100
200
300
400
500
DAYS OF TREATMENT Fig. 1. Biochemical data during long-term (500 days) administration of 1 a-OH-D3 in Patient 1,
initiation of hemodialysis when the serum creatinine reached 11.6 mg/dl, coincidental with established clinical criteria for severe irreversible end-stage renal failure:'; treatment with 1 c~-OH-D~ was started nine months after she had been on maintenance hemodialysis at which time clinical evidence of renal osteodystrophy (elevated parathyroid hormone and alkaline phosphatase levels and radiologic changes) had become apparent.' The primary renal disease in the second child was recurrent urinary tract infections and obstructive uropathy, the duration of follow-up at renal clinic was five years prior to maintenance hemodialysis. The predialysis serum creatinine was 13.2 mg/dl and the manifestations of renal osteodystrophy was present.' Treatment with I a-OH-D:~ was started concurrent with initiation of hemodialysis. Diphenylhydantoin 200 mg/day was also given to this patient, beginning on day 33 because of the recurrence of an idiopathic seizure disorder. The patients were dialyzed three times a week for four to six hours on the Ultra-Flo II disposable coil dialyzer. The calcium concentration in the dialysate was 6.0 mg/dl; magnesium concentration was 1.5 mEq/dl. Predialysis serum calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone levels were measured every second to fourth week. Roentgenograms of bones were obtained at regular intervals. Dietary reslric-
Fig. 2. Remineralization of the distal end of the left clavicle in Patient 1 showing resorption prior to treatment and improvement at 185 and 456 days. tions and the dosage of calcium supplement and phosphate-binding gel as previously described ~ remain the same throughout the study period. Radioimmunoassay of parathyroid hormone was performed according to the method of Arnaud and associates:~ The antiserum used, AS2-1/32, was obtained from Burroughs-Wellcome Laboratories, London, U.K. This antiserum has been previously shown to have immunologic specificity directed primarily toward the aminoterminal region of the PTH molecule.; The reference standard used was bovine PTH obtained from the Medical Research Council, Division of Biological Standards, National Institute for Medical Research, London, U.K. (code No. 71/324). The observed normal values were less than 400 pg/ml. Serum calcium, inorganic phosphorus, and alkaline phosphatase activity were measured by standard methods previously described? The study was approved by the Research Committee of the institution and informed consent obtained for each patient. RESULTS Biochemical data in Patient 1 are summarized in Fig. 1. The daily dosage of orally administered 1 a-OH-D3 were sequentially increased from 1 to 3 #g over the first 120
8 22
Chan,Oldham, and DeLuca
The Journal qf Pediatrics May 1977 e~o j GIVEN AFTER JEACH
...j
~./.g/day 4~ t,j
. . . . .
.
.
.
.
.
.
DIPHENYLHIt :E
~-
Z~ .a< ~.~--
NORMAL a.
O ~ Zw
=
E
NORMAL 0
loo
200
300
DAYS OF
400
soo
800
700
TREATMENT
Fig. 3. Biochemical data during long-term (700 days) administration of 1 a-OH-D3 in Patient 2. Interrupted lines indicate periods of medical noncompliance. days and maintained at 3 t~g/day for the next 120 days until hypercalcemia of 11 mg/dl (at 240 days) dictated a gradual reduction over the next 160 days to 1 ~g/day. The plasma iPTH began to show a definite downward trend from the ninetieth day of treatment in conjunction with plasma calcium increasing to normal levels. By the two hundred fortieth day, the iPTH was 19% of the pretreatment levels and was maintained at that level despite decreased dosage of 1 a-OH-D:, to 1 /~g/day. The plasma alkaline phosphatase returned to normal by two hundred fortieth day, and remained so for the rest of the study. The plasma phosphate failed to show a consistent trend. The radiologic changes observed with 1 a-OH-D~ therapy in Patient 1 are shown in Fig. 2. She developed persistent left shoulder pain three months prior to therapy and resorption of the distal end of the clavicle was documented in the pretreatment roentgenogram (Fig. 2). Evidence of healing was present within 185 days and continued improvement was maintained at 456 days. In addition, remineralization was associated with rapid relief of the left shoulder pain. Biochemical data in Patient 2 are summarized in Fig. 3. The daily dosage of orally administered 1 a-OH-D~ were serially increased from 1 to 4 #g. In addition, from the thirty-third day of therapy, she began receiving diphenylhydantoin (200 rag/day orally) because of a seizure
disorder. Plasma iPTH initially decreased to 75% of pretreatment levels at 90 days, then rose again to values which were even higher than pretreatment levels. There was no apparent correlation between plasma iPTH and plasma calcium concentrations, which were in the low normal range throughout most of the study period. Plasma phosphate levels increased, and alkaline phosphatase levels remained elevated.. Segmental roentgenograms of the left index finger from the same patient are shown in Fig. 4. There was advanced subperiosteal erosion of the distal phalanx prior to therapy. Remineralization and appearance of the distal tuft was apparent after 45 days of therapy, with further improvement at 153 days. The final roentgenogram, taken at 305 days of treatment, showed deterioration. On the five hundred sixtieth day, medical noncompliance was documented and the schedule was changed to 8 ~g grams after each hemodialysis to ensure medical compliance. She also admitted to noncompliance between 150 to 300 days. DISCUSSION The remarkable advancement in the past decade in defining the metabolic pathways and functions of vitamin D metabolites have clarified our understanding of the pathophysiology of renal bone disease and vitamin D resistant states. Short-term studies by Brickman and associates ~ for less than two weeks, with up to 2.7 ~g/day of the kidney hormone, 1-a-25-(OH)~D3, in four uremic adults, resulted in improved intestinal absorption of calcium and increased plasma calcium levels. Similar results were obtained by Chan and associates I in eight patients, using a synthetic analog, 1-a-OH-D3, at oral dosages of 1 to 4 #g/ day for up to 260 days. In addition, a significant reduction of iPTH levels during therapy was demonstrated.' Chalmers and associates, l~ Peacock and colleagues," Hirooka and associates, ~ and Balson and coworkers ':' independently documented the short-term action of 1-a-OH-D:~ directly on bone and intestine, but parathyroid activity was not reported. The lag period between administration of I-a-OH-D.~ and roentgenographic healing of rickets (45 to 185 days) in our cases is longer than that reported by Hirooka and associates ~2and Henderson and coworkers. ~ This may be related to variability of absorption of the vitamin analog or other yet undefined factors. The present study demonstrates that prolonged treatment with small amounts of 1-a-OH-D:, orally for up to 700 days can ameliorate the renal osteodystrophy as evidenced by sustained reduction of plasma iPTH levels, plasma alkaline phosphatase, radiologic evidence of healing, and subjective alleviation of bone pain. The complication of hypercalcemia is easily counteracted by reduc-
Volume 90 Number 5
Hydroxyvitamin D:~ with osteodystrophy and hemodialysis
823
Fig. 4. Radiologic changes in the right index finger of Patient 2 showing resorption of distal tuff prior to treatment and
improvement at 45 and 153 days. Deterioration and resorption of the distal tuft recurred at 305 days. tion of dosage and is not as severe as that described by Brickman and associates.~'using 1-a-25-(OH)~-D3. The less successful results in our second patient may, in part, be attributed to the anticonvulsant therapy she was receiving during the study period. A study on institutionalized mentally retarded children showed those receiving phenobarbital or diphenylhydantoin had lower concentration of 25-OH-vitamin D in their plasma.':' This, as well as other studies, suggests an interference by anticonvulsant medication on the normal metabolism of vitamin D. Since it appears that I-a-(OH)-D~ must be hydroxylated to Ia-25-(OH)~D:~ before it is physiologic active, TM factors which alter the formation of 25-OH-D~ from vitamin D:~ might be expected to alter the utilization of this synthetic analog. However, since evidence for increased bone mineralization in this patient was seen during the initial 153 days of therapy, despite concomitant anticonvulsant medication, the subsequent deterioration is more likely attributable to her medical noncompliance, which applies not only to the Ia-OH-D:. but extends to poor compliance of all dietary restrictions, as well as calcium supplementations, phosphate-binding gel, and" the diphenylhydantoin. Serum diphenylhydantoin levels were not measured so that consistent intake of this drug was not established. The sustained low levels of iPTH in Patient l for a period of 220 days (day 180 to 400, Fig. l) was related
primarily to the use of 1 a-OH-D3 and most likely contribute to the development of two episodes of hypercalcemia at 270 and 365 day s of therapy, respectively. However, the sustained correction of hypocalcemia via the hemodialysis procedures must be recognized. In conclusion, it should be emphasized that there are multiple factors contributing to the development of renal osteodystrophy? ............. The impaired production of the kidney hormone, 1-a-25-(OH)2D3, is only one of the major factors. The present study does, however, add further support to the efficacy and relative lack of complications in the prolonged use over two years of an analog of the active vitamin D metabolite in the treatment of renal osteodystrophy in patients who are receiving maintenance hemodialysis. The experience also points to the importance of iPTH levels as indices of adequacy of dosage levels. REFERENCES
1. Chan JCM, Oldham SB, Holick MF, and DeLuca HF: 1 ahydroxyvitamin D~ in chronic renal failure: A potent analogue of the kidney hormone, 1,25-dihydroxycholecalciferok JAMA 234:47, 1975. 2. Holick MF, Semmler EJ, Schnoes HK, and DeLuca HF: 1 a-hydroxy derivative of vitamin D3: A highly potent analog of la, 25-dihydroxyvitamin D3, Science 180:190, 1973. 3. Chan JCM, and Parrish AE: Maintenance pediatric hemodialysis: Principles and techniques, Clin Proc Child Hosp Natl Med Ctr 30:214, 1974.
82
49
5~
6
7 8 9
10
ll
,an, Oldham, and DeLuca
CM: Renal osteodystrophy in children, Clin Pediatr 1976. 7M: Dietary management of renal failure in infants 9 ;dren: principle of nutritional therapy and some ~,~ive diets, Clin Pediatr 12:707, 1973. , CD, Tsao HS, and Littledike ET: Radioimmuof human parathyroid hormone in serum, J Clin ,,'.~:21, 1971. and Singer FR: Radioimmunoassay for human :old hormone, Clin Chim Acta 54:161, 19749 9 M: The effect of milk formulae on acid balance, .~:~ab 16:140, 1974. .n AS, Coburn JW, and Norman AW: Action of ~'droxycholecalciferoL a potent, kidney-produced ~te of vitamin D~ in uremic man, N Engl J Med 1972. TM, Hunter JO, Davie MW, et al: 1 alpha,.holecalciferol as a substitute for the kidney 1,25-dihydroxycholecalciferol in chronic renal ~mcet 2:696, 1973. M, Callagher JC, and Nordin BEC: Action of l
The Journal of Pediatrics May 1977
12.
13.
14.
15.
16.
alpha-hydroxyvitamin D3 on calcium absorption and bone resorption in man, Lancet 1:385, 1974. Hirooka M, Wako H, Kaneko C, Ishikawa M, Sasaki S, and Suda T: Curative effects of 1 a-hydroxycholecalciferol on calcium metabolism and bone disease in patients with chronic renal failure, J Nutr Sci Vitaminol 21:277, 1975. Balsan S, Gatabedian M, Gorgniard R, Holick MF, and DeLuca HF: 1,25-dihydroxyvitamin D3 and l a hydroxyvitamin D3 in children: Biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance, Pediatr Res 9:586, 1975. Henderson RG, Russell RGG, Ledingham JFF, et al: Effects of 1,25 dihydroxycholecalciferol on calcium absorption, muscle weakness and bone disease in chronic renal failure, Lancet 1:379, 1974. Tolman KG, Jubiz W, Sannella JJ, Madsen JA, Belsey RE, Goldsmith RS, and Freston JW: Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children, Pediatrics 56:45, 1975. DeLuca HF: Proceedings of 1 lth European symposium on calcified tissue (1975) (in press).